Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): Structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel

J. Med. Chem. 2010, 53, 3645–3674 3645

DOI: 10.1021/jm100040c

Tetrahydrochromenoimidazoles as Potassium-Competitive Acid Blockers (P-CABs):

Structure-Activity Relationship of Their Antisecretory Properties and Their Affinity toward the

hERG Channel^†

‡

Andreas M. Palmer,*^,‡Vittoria Chiesa, Anja Schmid, Gabriela Munch, Burkhard Grobbel, Peter J. Zimmermann,

€

‡

€

Christof Brehm, Wilm Buhr, Wolfgang-Alexander Simon, Wolfgang Kromer, Stefan Postius, Jurgen Volz, and

Dietmar Hess^§

^‡NYCOMED GmbH, Departments of Medicinal Chemistry, Biochemistry, Pharmacology, and Physicochemistry, Byk-Gulden-Strasse 2,

D-78467 Konstanz, Germany, and ^§NMI TT GmbH, Markwiesenstrasse 55, D-72770 Reutlingen, Germany

Received January 13, 2010

Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of

acid-related diseases that are widespread and constitute a significant economical burden. Enantiomeri-

cally pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK

405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A

comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro

activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was

established. In addition, efficacy and duration of the antisecretory action was examined for the most

promising target compounds by 24 h pH-metry in the fistula dog and a significantly different SAR was

observed as compared to the Ghosh Schild rat. Several tetrahydrochromenoimidazoles were identified

that possessed a comparable profile as the candidate 4.

1. Introduction

treatment of GERD has focused on acid inhibition, specifi-

cally maintaining pH > 4 in the esophagus as long as

possible.⁷

Acid-related disorders are highly prevalent in the developed

world. They have a significant impact on patient quality of life

and are a major burden on health care systems. Gastric acid

was identified as an important pathogenic factor for a variety

of common gastrointestinal disorders such as duodenal ulcer

and gastresophageal reflux disease (GERD^a).⁷GERD has

emerged as the most important acid-related disorder. Medical

The principal stimulants of acid secretion are histamine,

gastrin, and acetylcholine. These agents interact with recep-

tors coupled to two major signal transduction pathways

(adenylate cyclase and intracellular calcium). Both the intra-

cellular cAMP and calcium-dependent signaling systems acti-

vate downstream kinases, ultimately leading to fusion and

activation of H^þ/K^þ-ATPase, the proton pump.⁷Because the

gastric proton pump is located at the end of the signaling

cascade, its inhibition is thought to be especially efficient

in controlling gastric acid secretion and the development of

H^þ/K^þ-ATPase inhibitors for the treatment of acid-related

diseases has attracted considerable interest.⁸

^†Design of novel P-CABs, Part VII, see refs 1-6.

*To whom correspondence should be addressed. Phone: þ49 7531 84

4783. Fax: þ49 7531 849 2087. E-mail: andreas.palmer@nycomed.com.

^aAbbreviations: APA, acid pump antagonist; cAMP, cyclic adeno-

sine monophosphate; CDI, carbonyldiimidazole; cpd; compound; CE,

capillary electrophoresis; DAIPEN, 1,1-di(4-anisyl)-2-isopropyl-1,2-

ethylenediamine; DIAD, diisopropylazodicarboxylate; DIPEA, diiso-

€

propylethylamine (Hunig’s base); DMAP, 4-dimethylaminopyridine;

A variety of heterocyclic structures has been described in

literature that inhibit the gastric proton pump either in an

irreversible or a reversible manner.⁸Irreversible proton pump

inhibitors (PPIs) are acid-activated prodrugs that covalently

bind to the gastric H^þ/K^þ-ATPase on its luminal surface.⁹

PPIs are very effective and safe drugs and have revolutionized

the treatment of acid-related diseases.¹⁰Nevertheless, they

have some shortcomings including short plasma residence

time, a delayed onset of action, incomplete acid suppression in

the majority of patients, and the need for ingestion before a

meal to achieve maximal efficacy.¹⁰An estimated 30-40% of

GERD patients continue to suffer from symptoms during PPI

treatment, which has stimulated the search for even more

effective drugs.¹¹Various K^þ-competitive inhibitors of the

pump, acid pump antagonists (APAs), or potassium-compe-

titive acid blockers (P-CABs) are being developed with the

DMF, dimethylformamide; DMSO, dimethylsulfoxide; ED₅₀, effective

dose (50% reduction of maximum effect); EDC-HCl, N-(3-

dimethylaminocarbonyl)-N⁰-ethylcarbodiimide hydrochloride; ee, en-

antiomeric excess; equiv, equivalent(s); ESI, electrospray ionization;

GERD, gastresophageal r_þeflux disease; h, hour(s); hERG, human ether-

a-go-go related gene; H /K^þ-ATPase, gastric proton pump; logD,

distribution coefficient between 1-octanol and aqueous KCl solution

(parameter for compound lipophilicity); MIBK, methylisobutyl ketone;

min, minute(s); mp, melting point; MsOH, methanesulfonic acid; n.d.,

not done; P-CAB, potassium competitive acid blocker; pIC₅₀, negative

logarithmic value of the compound concentration required to achieve

50% inhibition; pK_a, dissociation constant; PPI, proton pump inhibitor;

PVC, polyvinyl chloride; SAR, structure-activity relationship; S/C

ratio, substrate to catalyst ratio; SEM, trimethylsilylethoxymethyl;

TBTU, O-(1H-benzotriazol-1-yl)-N,N,N⁰,N⁰-tetramethyluronium tetra-

fluoroborate; TES, ethyltrimethylsilyl; THF, tetrahydrofuran; TMS,

tetramethylsilane; t_M, migration time; t_R, retention time; TdP, torsades

de pointes; Xyl-BINAP, 2,2⁰-bis(di(3,5-dimethylphenyl)phosphanyl)-

1,1⁰-binaphthyl; Xyl-P-Phos, 2,2⁰,6,6⁰-tetramethoxy-4,4⁰-bis[di(3,5-di-

methylphenyl)phosphino]-3,3⁰-bipyridinyl.

r

2010 American Chemical Society

Published on Web 04/09/2010

pubs.acs.org/jmc

3646 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

advantage of complete inhibition of acid secretion indepen-

dent of pump activity and improved acid control.⁹P-CABs

already bind to the resting pump, i.e., to its nonphosphory-

lated form in the absence of ATP.¹²Because of their reversible

mode of action, the duration of their antisecretory effect

directly depends on the drug’s serum concentration. Conse-

quently, P-CABs allow optimum control of pH elevation with

respect to both its duration and degree.¹³

One research area within Nycomed was focused on the

development of 3,6,7,8-tetrahydrochromenoimidazoles 2 as

potassium-competitive acid blockers (Figure 1). This hetero-

cyclic scaffold emerged from the systematic investigation of

possible variations of the well-known imidazo[1,2-a]pyridine

motif.⁵In comparison to the isomeric imidazo[1,2-a]pyridines

1, represented by 3 (BYK 311319),⁵the respective benzimi-

dazoles 2, represented by 4 (BYK 405879),^14,15possess a lower

pK_avalue, resulting in a more selective accumulation in the

parietal cell and a better safety profile. Enantiopure P-CABs

belonging to both structural classes can be prepared in an

analogous manner (asymmetric reduction of ketones followed

by Mitsunobu cyclization of the resulting diols), and the large

scale synthesis of the candidate 4 was based on this synthetic

strategy.^14-17Although the tetrahydrochromenoimidazole 4

constitutesa P-CAB withwell-balancedproperties, westudied

the SAR within this lead series in more detail focusing on (a)

optimum pharmacological activity in two species (Ghosh

Figure 1

Scheme 1^a

^aReagents and conditions: (i) Li[Et₃BH], THF, rt, 2 h, then NaOH, H₂O, then H₂O₂, 100% (crude); (ii) SO₃-pyridine, DMSO, Et₃N, rt, 3 h, 78%; (iii)

Dess-Martin periodinane, CH₂Cl₂, rt, 2 h, 49%; (iv) LiAlH₄, THF, rt, 1 h, 46%; (v) NaClO₂, NaH₂PO₄-H₂O, t-BuOH, 2-methylbut-2-ene, H₂O, 40 °C,

5 h, 91%; (vi) amide coupling, method 1, EDC-HCl, DMAP, CH₂Cl₂, HNR1R2 or HNR1R2-HCl, NEt₃, rt, 0.5-18 h, method 2, TBTU, DIPEA,

DMF, 40 °C, 0.5-1 h, then HNR1R2 or HNR1R2-HCl, 40 °C, 1-2 h or rt, 17 h, method 3, CDI, CH₂Cl₂, rt, 1-1.5 h, then HNR1R2, HOAc, rt, 4-17 h,

method 4, TBTU, DIPEA, HNR1R2 or HNR1R2-HCl, DMF, rt, 2 h, yields reported in Table 1; (vii) NaOH, ethylene glycol, 195 °C, 2 d (distillation of

H₂O), 80%; (viii) TBTU, DIPEA, DMF, 40 °C, 1 h, then acetohydrazide, 40 °C, 2 h, 75%; (ix) POCl₃, 50 °C, 1 h, 42%.

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3647

Table 1. Biological and Pharmacological Evaluation of Target Compounds with Different Carboxamide Residues

3648 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Table 1. Continued

Palmer et al.

^aYield of the coupling reaction of carboxylic acid 7 with the respective amine HNR1R2. ^bpIC₅₀value of the inhibition of H^þ/K^þ-ATPase derived

from hog gastric mucosa (competitive binding assay). ^cpIC₅₀value of the inhibition of ¹⁴C-dimethylaminopyridine accumulation in intact gastric glands

isolated from New Zealand rabbits. ^dPentagastrin-stimulated acid secretion of the perfused rat stomach (Ghosh Schild rat): ED₅₀(μmol/kg) or dose

(μmol/kg)/reduction (%). ^e% inhibition of the hERG channel in the presence of 10 μM of the respective API (whole-cell patch-clamp technique).

^fDistribution coefficient between 1-octanol and aqueous KCl solution determined at 25 °C by potentiometric titrations in the range of pH 2.0-11.0.

^gLogarithmic partition coefficient determined at 37 °C by reversed phase HPLC using seven substances with known logD as reference. ^hDetermined by

potentiometric cosolvent titrations in 0.15 mol/L KCl solutions in the range of pH 2.0-11.0 at 25 °C using methanol as cosolvent. ⁱThe synthesis of BYK

405879 (4) is reported in lit.^{15 j}Synthesis via asymmetric reduction of the respective ketone precursor and subsequent Mitsunobu cyclization of the

obtained diol (see Scheme 2, Table 2). ^kPrepared by oxidation of sulfide 30 with sodium periodate (MeOH, H₂O, rt, 1 h).

Schild rat and fistula dog) and (b) low affinity toward the

hERG channel. The primary objective of the study was to

identify P-CABs with a longer duration of action in the fistula

dog than the current candidate 4.

satisfactory manner by the administration of irreversible

proton pump inhibitors.⁷

(b) In recent years, a number of drugs have been with-

drawn from the market due to cardiovascular toxicity

associated with blockade of the hERG channel. The human

ether-a-go-go related gene (hERG) potassium channel

plays a key role in regulating cardiac excitability and

maintenance of normal cardiac rhythm.^18,19The inhibi-

tion of potassium channels encoded by hERG is con-

sidered as the main mechanism underlying an acquired

long QT syndrome and a potentially fatal arrythmia called

“torsades de pointes” (TdP).¹⁹Although the risk of cardio-

vascular toxicity cannot be assessed merely on basis of

in vitro hERG assays, such assays form a key element in

the assessment of TdP liability, with patch-clamp electro-

physiology as gold standard.^20,21hERG channels exhibit

a unique susceptibility to pharmacological inhibition by

therapeutically and chemically diverse drugs. Despite

considerable computational and statistical modeling efforts

and studies on hERG, the knowledge of how known ligands

bind to hERG remains fragmentary and a structure-

activity relationship has to be established within each

chemical series.^19,20,22,23

(a) Theprimarygoalofthe firstpharmacological model, the

Ghosh Schild rat, is to determine the ED₅₀value of the

respective drug substance.¹³This value reflects the dose by

which the maximum amount of pentagastrin-stimulated acid

output is reduced by 50%. The acid output is measured for

a period of 3.5 h after administration of the P-CAB. A

preliminary assessment whether the antisecretory effect of

the drug substance is long-lasting is already possible from

the analysis of the shape of the titration curve. However,

the fistula dog constitutes a more suitable pharmaco-

logical model for the determination of the duration of

acid suppression. The dogs used for these investigations

received special surgery that allows the introduction of a

pH-electrode into their stomach and the determination of

their intragastric pH value over a period of several hours

after administration of the drug substance.¹³The identi-

fication of P-CABs which are able to increase the intra-

gastric pH to a value of >5 for at least 6-8 h is a major

goal. Such substances should be useful for the treatment of

night-time GERD, a phenomenon having a severe impact

on patients’ quality of life which cannot be treated in a

This publication provides a comprehensive overview over

the SAR in the class of tetrahydrochromenoimidazoles 2

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3649

Scheme 2^a

^aReagents and conditions: (i) Eschenmoser’s salt, CH₂Cl₂, rt, 3 h; (ii) 1-(1-arylvinyl)pyrrolidine, toluene or 1,2-dimethoxyethane, 80-100 °C, 1-6 h,

yields reported in Table 2 (method A); (iii) 2,2-dimethoxypropane, MsOH, CH₂Cl₂, rfl., 16 h, 64 (ArdPh) 92%, 65 (Ard2-MeC₆H₄) 96%; (iv)

KOH, MeOH, H₂O, 55 °C, 16 h, 66 (ArdPh) 99%, 67 (Ard2-MeC₆H₄) 99%; (v) TBTU, DIPEA, DMF, rt, 1 h, then amine, rt, 2 h; (vi) 1 N HCl, THF, 50

°C, 2-6 h, yields reported in Table 2 (method B); (vii) LiAlH₄, THF, rt, 2 h, 90%; (viii) SOCl₂, CH₂Cl₂, 0 °C, 1.5 h, 100%; (ix) NaOMe, MeOH, 50 °C,

0.5 h, 95%; (x) RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN] (S/C = 100:1 to 500:1), 1.1-2.75 equiv t-BuOK (1 M solution in t-BuOH), 25-80 bar H₂,

65-80 °C, 16-20 h, yields and optical purities reported in Table 2; (xi) PPh₃, DIAD, THF, rt, 5 min-18 h, yields and optical purities reported

in Table 2.

covering their physicochemical and biological properties,

their affinity toward the hERG channel, and their pharma-

cological efficacy in the Ghosh Schild rat and the fistula

dog.^24-26

manner following the indirect approach illustrated in

Scheme 1. The reduction of carboxamide 4 using lithium

triethylborohydrideaffordedthe correspondingalcohol5 that

was oxidized to the aldehyde 6 using either sulfurtrioxide

pyridine complex (Parikh-Doering conditions) or Dess-

Martin periodinane.²⁷The sulfurtrioxide pyridine complex

was the preferred reagent because the product 6 could be

isolated by a simple crystallization step. In the case of the

Dess-Martin oxidation, the aldehyde 6 had to be purified by

column chromatography. Alternatively, aldehyde 6 was pre-

pared by reduction of carboxamide 4 with lithium aluminum

hydride. However, the two-step procedure (reduction of

carboxamide 4 to alcohol 5 and subsequent oxidation) was

preferred because the reactions could be controlled more

easily on a larger scale. Finally, the carboxylic acid 7 was

obtained in >90% yield using sodium chlorite as oxidizing

2. Chemistry

For the synthesis of the first series of target compounds

(aryl = 2-methylphenyl), the readily available carboxamide 4

was used as starting material. Hydrolysis of the amide func-

tion present in 4 and further transformation of the carboxylic

acid intermediate 7 can provide access to tetrahydro-

chromenoimidazoles bearing a variety of residues NR1R2

(Scheme 1). In the beginning, a suitable method for the direct

hydrolysis of the carboxamide residue was not available.

However, the carboxylic acid 7could be prepared in a convenient

3650 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Table 2. Synthesis of Target Compounds 21, 25, 39, 43, 104-120

Palmer et al.

^aThe reported yields relate to Scheme 2, steps (i) and (ii), method A, or steps (v) and (vi) / step (vi) in the case of ketone 81, method B. ^bThe reported

yields and optical purities relate to Scheme 2, step (x). ^cThe reported yields and optical purities relate to Scheme 2, step (xi). ^dThe synthesis has been

described in lit.^{14 e}Increase of optical purity by subsequent crystallization in the presence of mandelic acid.

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3651

agent (Kraus oxidation).²⁸Later it was found that the direct

saponification of the carboxamide residue could be achieved

by heating a solution of the substrate 4 and sodium hydroxide

in ethylene glycol to 190 °C and removal of water (present in

the reagents/solvent) by destillation.²⁹A variety of target

compounds 8-40 was prepared by condensation of the

carboxylic acid 7 with different amines using EDC-HCl,

TBTU, or CDI as coupling agent (Table 1). The tetrahydro-

chromenoimidazole, 42, bearing a 2-methyl-1,3,4-oxadiazole

substituent, was obtained in two steps from carboxylic acid 7

(Scheme 1). Condensation of carboxylic acid 7 with acetohy-

drazide afforded intermediate 41, which was heated in phos-

phorus oxychloride, affording the carboxamide isoster 42 in

42% yield.

To examine the influence of the aryl residue on the phar-

macological activity and the hERG affinity of the respective

benzimidazole derivative, a similar approach was pursued

as previously described for the candidate 4 (Scheme 2,

Table 2).^14,15The prochiral ketones 47-61 were prepared by

transformation of the Mannich base 46 with different

1-(1-arylvinyl)pyrrolidines. Ketones 62 and 63, containing a

carboxylic ester moiety, were used as versatile intermediates

for rapid variation of the carboxamide moiety and as starting

material for the synthesis of the 5-methoxymethylene-substi-

tuted target compound 43. For these purposes, the oxo

function was protected by conversion of the ketones 62 and

63 into their acetals 64 and 65. The ester moiety of 64 and 65

was saponified and the respective carboxamide residue was

introduced by TBTU mediated coupling of the carboxylic

acids 66 and 67 with different amines. Finally, the prochiral

ketones 73-77 were prepared by acid-catalyzed cleavage of

their acetal precursors 68-72. Alternatively, the carboxylic

ester 65 was reduced with lithium aluminum hydride and the

obtained alcohol 78 was activated with thionyl chloride. The

methoxymethylene function was installed by nucleophilic

substitution of the resulting chloride 79 with sodium methy-

late. Again, acid-catalyzed cleavage of acetal 80 afforded the

required prochiral ketone 81. Noyori asymmetric hydro-

genation of the respective ketones 47-61, 73-77, and 81

in the presence of RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN] 82

(Figure 2) afforded the alcohols 83-103, typically in 80-

98% ee.^14,30-34The synthesis of the target compounds 21, 25,

39, 43, and 104-120 was then completed by Mitsunobu

cyclization of the diols 83-103 using triphenylphosphine

and DIAD (Table 2). In the 4-chlorophenyl series and in the

4-chloro-2-methylphenyl series, a variation of the carboxa-

mide residue CONR1R2 was performed by applying the

methods discussed in Scheme 1 (Scheme 3).

The 2-cyclopropyl-substituted benzimidazole 139 was pre-

pared following the synthetic route described previously

for the candidate 4 (Scheme 4).¹⁵The prochiral ketone 134

was obtained by conversion of Mannich base 132 with

ethyl 3-(2-methylphenyl)-3-oxopropanoate and subsequent

saponification and decarboxylation of intermediate 133. To

reduce the amount of hydrogenation catalyst and to enhance

the optical purity of the alcohol 137, the phenolic hydroxy

group was protected by conversion of hydroxyketone 134

with benzyl bromide. The asymmetric hydrogenation of the

Figure 2

Scheme 3^a

^aReagents and conditions: (i) Li[Et₃BH], THF, rt, 2 h, then NaOH, H₂O, 0 °C, 20 min, then H₂O₂, 0 °C, 0.75 h, 121 95% (crude), 122 72% (crude); (ii)

SO₃-pyridine, DMSO, NEt₃, rt, 16-17 h, 123 96%, 124 62%; (iii) NaClO₂, NaH₂PO₄-H₂O, t-BuOH, 2-methyl-2-butene, H₂O, 45 °C, 20 h, 125 97%, 126

100% (crude); (iv) TBTU, DIPEA, DMF, 40-45 °C, 0.75-1 h, then 127 methylamine, rt, 16 h, 73%, 128 azetidine, 40 °C, 1 h, 72%, 129 methylamine, rt,

16 h, 53%, 130 azetidine, rt, 16 h, 53%, 131 3-methoxyazetidine, rt, 16 h, 47%.

3652 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

benzyl-protected ketone 135 proceeded smoothly at a sub-

strate to catalyst ratio of 1000:1, and the alcohol 136

was isolated in 90% yield and 95.4% ee. Finally, the protec-

ting group was removed by catalytic hydrogenation and

the resulting diol 137 transformed to the target compound

138 under Mitsunobu conditions. The chemical purity of

the tetrahydrochromenoimidazole 138 was enhanced by crys-

tallization in the presence of succinic acid affording the

salt 139.

The synthesis of the 2-hydroxymethyl analogue 140 of

the candidate 4 has been described previously.³⁵The corres-

ponding 2-methoxymethyl-substituted benzimidazole deriva-

tive 142 was prepared by activation of the hydroxy function

of 140 with thionyl chloride and subsequent nucleophilic

substitution of the chloro atom of intermediate 141 with

methanol (Scheme 5).

The 3-NH analogue 150 of the candidate 4 was also

prepared (Scheme 6). The benzimidazole nitrogen atom was

protected using the SEM protecting group in an early stage of

this synthesis. To this end, building block 143 was alkylated

with 2-(trimethylsilyl)ethoxymethyl chloride, furnishing the pro-

tected analogue 144 in 39% yield. The carboxamide residue

was then introduced by palladium-catalyzed cross coupling of

bromobenzimidazole 144 with carbonmonoxide and dimethy-

lamine affording intermediate 145. The 4-hydroxybenzimidazole

146, obtained by hydrogenolytic cleavage of the benzyl pro-

tecting group present in 145, was used as starting material for

the reaction sequence described earlier (synthesis and asym-

metric reduction of ketone 147, Mitsunobu cyclization of the

resulting diol 148 to the tetrahydrochromenoimidazole 149).

The hydrogenation step proceeded with excellent enantios-

electivity (96% ee), and the high optical purity was maintained

in the course of the Mitsunobu reaction. Finally, the SEM

protecting group was removed by treatment of 149 with boron

trifluoride and the target compound 150 was obtained in

quantitative yield.

Scheme 4^a

3. Biological and Physicochemical Evaluation of the Target

Compounds

3.1. Assays for the Determination of Biochemical and

Pharmacological Activity. The biological and pharmacolo-

gical activity of the target compounds was determined using

the assays described previously.^5,13,36

First, the inhibitory activity against H^þ/K^þ-ATPase isolated

from hog gastric mucosa was assessed using a competitive

binding assay.^5,36When comparing the pIC₅₀values of the

tetrahydrochromenoimidazole target compounds with those

obtained for other P-CABs, it has to be considered that

the enzymatic activity depends on the pK_avalue of the respective

inhibitor. Because the assay is conducted at pH 7.4 and the

inhibition of the enzyme is caused by the protonated hetero-

cycle, typically lower pIC₅₀values are obtained for the less basic

benzimidazoles (pK_a∼ 5.8) as compared to their imidazo[1,2-

a]pyridine analogues (pK_a∼ 6.8).

Second, the cellular activity of the respective tetrahydro-

chromenoimidazole was assessed from the reduction of the

accumulation of the weak base ¹⁴C-dimethylaminopyri-

dine in intact gastric glands isolated from New Zealand

rabbits.^5,36The pIC₅₀values reported in Tables 1, 3, and 4

constitute the geometric mean from 4 to 5 measurements.

The standard deviation amounts to 0.1-0.2 log units.

Finally, the reduction of the acid output in the Ghosh

Schild rat was determined as a parameter for the in vivo

activity of the respective P-CAB.^5,13,36In this model, fasted

female Sprague-Dawley rats were anesthetized with urethane.

A PVC tube was inserted into the stomach via the esophagus,

^aReagents and conditions: (i) ethyl 3-(2-methylphenyl)-3-oxopro-

panoate, potassium tert-pentylate, DMF, toluene, 60 °C, 5 h; (ii)

Cs₂CO₃, MeOH/H₂O, 85 °C, 4 h, Σ37%; (iii) benzyl bromide, K₂CO₃,

DMF, 55 °C, 4 h, 51%; (iv) RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN]

(S/C = 1000:1), t-BuOK, H₂(80 bar), 2-PrOH, t-BuOH, 70 °C, 17 h,

90%, 95.4% ee; (v) Pd/C, H₂(1 bar), EtOH, rt, 18 h, 95%; (vi) PPh₃,

DIAD, THF, rt, 0.5 h; (vii) succinic acid, MIBK, 80 °C, 0.75 h, rt, 17 h,

Σ74%, 95.6% ee.

Scheme 5^a

^aReagents and conditions: (i) SOCl₂, CH₂Cl₂, rt, 2 h, 98%; (ii) NaOMe, MeOH, 65 °C, 17 h, 45%.

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3653

Scheme 6^a

^aReagents and conditions: (i) SEMCl, Et₃N, DMF, CH₂Cl₂, rt, 5 h, 39%; (ii) Pd(OAc)₂, PPh₃, HNMe₂, CO (6 bar), THF, 120 °C, 60 h, 72%; (iii) Pd/

C, H₂(5 bar), EtOH, rt, 16 h, 93%; (iv) (a) Eschenmoser’s salt, CH₂Cl₂, rt, 7 h, (b) 1-[(2-methylphenyl)vinyl]pyrrolidine, 1,2-dimethoxypropane, 85 °C,

3 h, 20%; (v) RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN], t-BuOK, H₂(25 bar), 2-PrOH, t-BuOH, 65 °C, 16 h, 70%, 95.8% ee; (vi) PPh₃, DIAD, THF, rt,

10 min, 45% (mixture with Ph₃PdO); (vii) BF₃-OEt₂, CH₂Cl₂, rt, 3 h, quant, 96.1% ee.

and the stomach was perfused with saline. A second tube

draining the pylorus was inserted through the abdominal wall

for collection of gastric secretion. Acid secretion was deter-

mined at 15 min intervals by titration of the perfusate with

NaOH. Gastric secretion was stimulated during a period of

4.5-5 h by an intravenous infusion of pentagastrin starting

after determination of 2 basal values of acid secretion (t = 30

min). After 1 additional h, the P-CAB was administered

intraduodenally (t = 90 min). The maximum inhibition was

defined as the maximum difference between the acid output in

the presence of the test drug and in the respective controls. The

ED₅₀value reflects the dose of the inhibitor that causes 50%

reduction of the pentagastrin-stimulated acid output.

For the most promising target compounds, efficacy and

duration of the antisecretory activity was determined in the

fasted fistula dog.¹³In this model, surgery was performed on

male Beagle dogs and a metallic fistula was placed in the left

side of the abdomen of the lowest part of the distal gastric

corpus region near the greater curvature. Gastric acid secre-

tion was stimulated one hour after beginning of continuous

pH-metry by subcutaneous infusion of pentagastrin cover-

ing a 22.5 h period. Drugs or vehicle were administered orally

as capsules 2.5 h after the start of the pH-metry (i.e., 1.5 h

after onset of pentagastrin infusion). Capsules were used to

guarantee that the full dose of the respective inhibitor

reached the stomach of the dog. In the stomach, the P-

CAB was released over a period of 3-5 min from the capsule.

The intragastric pH was continuously recorded for 24 h by

means of a combined glass electrode connected to an ambu-

latory pH meter.

3.2. Influence of the Carboxamide Substituent on hERG

Inhibition and Pharmacological Activity. Biological and

Pharmacological Activity. In the azetidine series, significant

inhibition of the gastric proton pump was observed only for

the parent compound 8 (Table 1, entry 2) or if the azetidine

ring contained a lipophilic substituent, e.g., fluoro or alkoxy

(P-CABs 9-13, entries 3-7). Substitution of the azetidine

moiety with a hydrophilic residue, e.g., hydroxy (target com-

pounds 14 and 15, entries 8 and 9) or carboxamide

(benzimidazoles 18 and 19, entries 12 and 13) or quarterniza-

tion (compounds 16 and 17, entries 10 and 11) resulted in a loss

of in vitro and in vivo activity. The unsubstituted carboxamide

20 (NR1R2=NH₂, entry 14) showed little affinity toward H^þ/

K^þ-ATPase. In contrast, significant inhibitory activity was

observed for a number of tetrahydrochromenoimidazoles be-

longing to the alkyl series (21-24, entries 15-18) and cyclo-

propyl series (25-26, entries 19 and 20). Further modifications,

including the oxidation (27, entry 21, NR1R2 = 2-oxopropyl)

or dehydrogenation (28, entry 22, NR1R2 = 2-propinyl) of the

propyl side chain were also tolerated. Interestingly, the activity

of the target compounds 28 and 29 containing the isosteric

2-propinyl and cyanomethyl substituents differed significantly

(entries 22 and 23). The incorporation of a sulfur or oxygen

heteroatom into the alkyl side chain resulted in compounds

with reduced antisecretory properties (30-31, 35-36, entries

24, 25 and 29, 30). Likewise, the carboxamides 32-34 contain-

ing heterocyclic residues did not possess a favorable profile

(entries 26-28). In the case of the N-methoxy-substituted

carboxamides 37 and 38, the alkylation state of the nitrogen

atom had a great impact on the P-CAB activity (entries 31 and

32). Whereas the secondary amide 37 only possessed weak

antisecretory properties, its tertiary analogue 38 showed note-

worthy inhibitory activity in the gastric glands and in the

Ghosh Schild rat. Ring extension from azetidine (8, entry 2)

to pyrrolidine (39, entry 33) was tolerated. However, the

incorporation of an oxygen atom into the pyrrolidine moiety

(morpholine 40, entry 34) resulted in reduced inhibition of the

gastric proton pump. It was also examined briefly whether the

hERG tail currents were recorded from stably trans-

fected CHO-K1 cells using the whole-cell patch-clamp

technique to test for a blockade of a test compound at

10 μM. Each compound was applied to three different

cells. The relative blockade of the tail current amplitude

was calculated and presented as arithmetic mean. In

general, the standard deviation of the single compounds

did not exceed 7%.

3654 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

Table 3. Biological and Pharmacological Evaluation of Target Compounds with Different Carboxamide and Aryl Residues

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3655

Table 3. Continued

^apIC₅₀value of the inhibition of H^þ/K^þ-ATPase derived from hog gastric mucosa (competitive binding assay). ^bpIC₅₀value of the inhibition of

¹⁴C-dimethylaminopyridine accumulation in intact gastric glands isolated from New Zealand rabbits. ^cPentagastrin-stimulated acid secretion of the

perfused rat stomach (Ghosh Schild rat): ED₅₀(μmol/kg) or dose (μmol/kg)/reduction (%). ^d% inhibition of the hERG channel in the presence of 10 μM

of the respective API (whole-cell patch-clamp technique). ^eDistribution coefficient between 1-octanol and aqueous KCl solution determined at 25 °C by

potentiometric titrations in the range of pH 2.0-11.0. ^fLogarithmic partition coefficient determined at 37 °C by reversed phase HPLC using seven

substances with known logD as reference. ^gDetermined by potentiometric cosolvent titrations in 0.15 mol/L KCl solutions in the range of pH 2.0 to pH

11.0 at 25 °C using methanol as cosolvent.

P-CAB properties were maintained if the typical carboxamide

residue R5 was replaced by other structural motifs. Target

compound 42, containing a 2-methyl-1,3,4-oxadiazole ring,

showed significant cellular activity and possessed an ED₅₀

value of 0.6 μmol/kg in the Ghosh Schild rat. Likewise, the

ether derivative 43 possessed very favorable antisecretory

properties.

residue to a carbonyl group showed little influence on the hERG

inhibitory activity (23 vs 27, entries 17 and 21). Comparison of

the hERG data obtained for the isosteric amides 28 (R1 =

propinyl) and 29 (R1 = cyanomethyl) clearly illustrates the

importance of the lipophilicity of the side chain (entries 22 and

23). The hERG data obtained for the sulfide 30 and the sulfoxide

31 provides further evidence that the lipophilicity of the carbox-

amide residue plays an important role (entries 24 and 25). At a

dose of 10 μM, the lipophilic sulfide 30 (logD(HPLC) = 3.2)

causes 73% inhibition of the hERG channel. The hERG affinity

is reduced to 6% if the sulfide group is oxidized to the corre-

sponding sulfoxide derivative 31. The lipophilic tetrahydro-

furano- and tetrahydropyrano-substituted carboxamides 33

(logD(HPLC) = 3.0) and 34 (logD(HPLC) = 3.3) also showed

high affinity to the hERG channel (entries 27 and 28). The

alkylation state of the nitrogen atom of the carboxamide residue

also plays a role, e.g., the secondary amide 35 (entry 29) causes

significantly stronger inhibition of the hERG channel than its

tertiary analogue 36 (entry 30). However, the trend that second-

ary amides enhance the affinity toward the hERG channel (in

comparison to their tertiary analogues) is not general (cf. the

secondary amide 37 with its tertiary analogue 38, entries 31 and

32). The increase of size of the cyclic amine NR1R2 is accom-

panied by enhanced affinity toward the hERG channel (cf.

azetidine 8, logD(HPLC) = 2.8, and pyrrolidine 39, logD-

(HPLC) = 3.1, entries 2 and 33). On the other hand, the hERG

inhibition can be reduced by incorporation of a heteroatom into

the cyclic residue NR1R2 (cf. pyrrolidine 39, logD(HPLC) =

3.1, and morpholine 40, logD(HPLC) = 2.8, entries 33 and 34).

Despite the rather high lipophilicity of target compounds 42

(logD(HPLC) = 3.3) and 43 (logD(HPLC) = 3.4), containing a

hERG Inhibition. The affinity of the respective tetrahydro-

chromenoimidazole toward the hERG channel strongly depends

on the geometry and the lipophilicity of the residue NR1R2

(Table 1). This is reflected by the data obtained for the azetidino

series. If the azetidine ring does not contain any substituents at all

(8, logD(HPLC) = 2.8, entry 2) or a hydrophilic residue (14-16,

18-19, logD(HPLC) = 2.3-2.5, entries 8-10, 12, and 13), less

than 15% hERG inhibition was observed at a dose of 10 μM.

The same trend is visible by comparing the alkoxy-substituted

azetidines 11 (R = OMe, logD(HPLC) = 2.9, entry 5), 12

(R = OEt, logD(HPLC) = 3.0, entry 6), and 13 (R = OPr,

logD(HPLC) = 3.3, entry 7): With increasing size of the alkoxy

group, the hERG inhibition observed in the presence of 10 μMof

the respective P-CAB increased from 18% to 94%. In the series

of the alkyl-substituted carboxamides 20-24 (entries 14-18),

the hERG inhibition was determined by both, the size (cf.

n-propyl 23 vs methyl 21 and hydrogen 20) and the geometry

(cf. i-propyl 24 vs n-propyl 23) of the alkyl group. Ring closure,

i.e., the transition from isopropyl 24 to cyclopropyl 25, slightly

increased the affinity to the hERG channel (compare entries 18

and 19). On the other hand, a strong increase of hERG inhibition

occurred when a methylene spacer was introduced between the

nitrogen atom and the cyclopropyl ring (25 vs 26, entries 19 and

20). The oxidation of the methylene group of the n-propyl

3656 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

Table 4. Biological and Pharmacological Evaluation of Target Compounds with Different Substituents Attached to the Imidazole Ring

H^þ/K^þ-ATPase

Gastric

Ghosh Schild

hERG^d%

logD

logD^f

Entry Cpd.

R3

Me

R4

pIC₅₀

Glands pIC₅₀rat ED₅₀[μmol/kg]^cinhib @ 10 μM (pH 7.4)^e(HPLC, pH 7.4)

pK_a

5.68

a

b

g

1

2

3

4

5

4

139 c-Pr

140 CH₂OH

Me

5.3

6.1

0.23

0.1

1.0

3.0

0.5

33

6

2.52

2.84

n.d.

2.82

2.8

3.3

2.5

2.9

2.8

n.d.

4.57

5.59

n.d.

5.93

4.34

5.71

5.28

n.d.

12

7

142 CH₂OMe Me

150 Me

H

11

5.66, > 11.8

^apIC₅₀value of the inhibition of H^þ/K^þ-ATPase derived from hog gastric mucosa (competitive binding assay). ^bpIC₅₀value of the inhibition of ¹⁴C-

dimethylaminopyridine accumulation in intact gastric glands isolated from New Zealand rabbits. ^cPentagastrin-stimulated acid secretion of the

perfused rat stomach (Ghosh Schild rat): ED₅₀(μmol/kg) or dose (μmol/kg)/reduction (%). ^d% inhibition of the hERG channel in the presence of 10 μM

of the respective API (whole-cell patch-clamp technique). ^eDistribution coefficient between 1-octanol and aqueous KCl solution determined at 25 °C by

potentiometric titrations in the range of pH 2.0-11.0. ^fLogarithmic partition coefficient determined at 37 °C by reversed phase HPLC using seven

substances with known logD as reference. ^gDetermined by potentiometric cosolvent titrations in 0.15 mol/L KCl solutions in the range of pH 2.0-11.0

at 25 °C using methanol as cosolvent.

2-methyl-1,3,4-oxadiazole ring or a methoxymethylen group in

lieu of the carboxamide residue, these derivatives showed a

moderate interaction with the hERG channel (comparable to

the N,N-dimethylcarboxamide 4).

3.3. Influence of the Aryl Substituent on hERG Inhibition

and Pharmacological Activity. As in the case of the carbox-

amide substituent, the choice of the aryl moiety had a

significant influence on the biological and pharmacological

activity of the target compounds and their affinity toward

the hERG channel (Table 3).

the introduction of the fluoro atom did not exert any

influence on the affinity of the target compound toward

the hERG channel (entry 12 vs 1), the presence of the chloro

atom resulted in a strongly enhanced inhibition of hERG

(entry 13 vs 1).

Interestingly, upon introduction of an additional ortho-

methyl substituent, the excellent in vitro and in vivo potency

was maintained in both series (114 and 115, entries 16 and 17

vs 112 and 113, entries 12 and 13), whereas a significant

reduction of hERG binding was observed, especially in the

chloro series. Because the presence of the chloro atom

seemed to be highly beneficial for the efficacy of the target

compounds as P-CABs further carboxamide residues were

studied in the 4-chlorophenyl and the 4-chloro-2-methyl-

phenyl series (127 and 128, entries 14 and 15/129-131,

entries 18-20). Although a high degree of cellular activity

and in vivo efficacy was maintained upon replacement of the

dimethylamine residue by methylamine or azetidine, in some

cases a decrease of the pIC₅₀value determined in the

competitive binding assay against H^þ/K^þ-ATPase was obse-

rved. On the other hand, the primary goal to reduce hERG

binding by variation of the carboxamide residue was not

achieved in the 4-chlorophenyl series. In the case of aryl =

4-chloro-2-methylphenyl, the dimethylcarboxamide resi-

due was found to exert an unique influence on the hERG

channel because an increase of hERG inhibition was obse-

rved for the other carboxamide analogues studied. This

effect was especially pronounced for the 3-methoxyazeti-

dine substituent: the respective target compound 131

caused complete inhibition of the hERG channel at a dose

of 10 μM. Generally it is thought that changes in lipo-

philicity can contribute significantly to hERG binding.

However, in the present case, the different affinity toward

hERG cannot be explained by this parameter because

almost identical logD values were determined for all of

the target compounds 115 and 129-131 prepared in the

4-chloro-2-methyl series(logD= 3.40-3.46, logD(HPLC) =

3.1-3.2).

The introduction of a methyl substituent in ortho-position

of the phenyl moiety consistently increased the cellular

activity of the target compounds in a magnitude of 0.5 log

units (cf. entries 1-6, 4 vs 104, 21 vs 105, and 8 vs 106). The

increase in potency was accompanied by a slight increase in

lipophilicity (Δ logD(HPLC) = 0.2-0.3). In two cases, also

a higher affinity toward the gastric proton pump enzyme was

observed (Δ pIC₅₀= 0.3-0.6). On the other hand, a uniform

trend with regard to the pharmacological activity in the

Ghosh Schild rat and the inhibition of the hERG channel

was not visible.

Other substituents (apart from the methyl group) were

also tolerated in the ortho position of the phenyl ring.

Replacement of the methyl group by a fluoro atom (107,

entry 7), a chloro atom (108, entry 8), or an ethyl group (109,

entry 9) was accompanied only by a minor loss of cellular

activity (Δ pIC₅₀= 0.2-0.3) and a slight change in lipophi-

licity (Δ logD(HPLC) = -0.1 to 0.2). In the same manner, a

small increase in dose (from 0.23 μmol/kg to 0.4-0.5 μmol/

kg) was required to achieve 50% reduction of the pentagas-

trin-stimulated acid output in the Ghosh Schild rat. Bulky

alkyl substituents were not tolerated in ortho position of the

phenyl ring and caused a reduction of both the in vitro and in

vivo efficacy (e.g., cylopropyl derivative 110, entry 10).

Likewise, target compound 111, possessing an ortho-meth-

oxymethylene group, showed little biological and pharma-

cological activity (entry 11).

Para-substitution of the phenyl moiety with halide atoms

turned out to be highly beneficial, especially with regard

to cellular activity and in vivo efficacy in the Ghosh Schild

rat (112 and 113, entries 12 and 13 vs 104, entry 1). Whereas

Target compounds 116 and 117 carrying two halide sub-

stituents in ortho- and para-positions of the phenyl moiety

were also prepared (entries 21 and 22). These compounds

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3657

Table 5. Comparison of the Pharmacological Activity of Selected 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazoles in the Ghosh Schild Rat and the

Fistula Dog

showed high cellular activity and potent antisecretory prop-

erties in the Ghosh Schild rat, comparable to their respective

2-methyl analogues (116, entry 21 vs 114, entry 16, 117, entry

22 vs 115, entry 17). However, in terms of hERG binding, the

ortho-methylphenyl motif seemed to offer certain advan-

tages over the ortho-chlorophenyl residue (117, entry 22 vs

115, entry 17).

From the data obtained for the naphthyl-substituted

target compound 118, it can be concluded that sterically

demanding aryl substituents compromise the biological and

pharmacological activity (entry 23). On the other hand, this

highly lipophilic moiety (logD = 3.37) might account for the

enhanced affinity of tetrahydrochromenoimidazole 118 to-

ward the hERG channel.

The isosteric replacement of the phenyl moiety against

a thiophene substituent was also investigated. In the case of

the 2-thienyl ring, this modification was accompanied by a

strong decrease of the in vitro and in vivo activity of the

respective target compound 119 (cf. entries 24 and 1). As

exemplified by benzimidazole 120, the position of the sul-

fur atom in the aromatic ring seems to be crucial. The

replacement of the 2-methylphenyl motif by a 2-methyl-

3-thienyl ring was well tolerated, and both compounds 120

and 4 possessed similar cellular activity and pharmacological

properties (entry 25 vs 2). In terms of affinity toward the

gastric proton pump enzyme and the hERG channel, the

thiophene derivative 120 even offered certain advantages

over the candidate 4.

3.4. Influence of the Imidazole Substitution Pattern on

hERG Inhibition and Pharmacological Activity. The SAR of

the substituents attached in 2- and 3-position of the imidazole

ring was also studied briefly. The data reported in Table 4

clearly indicates that this position is highly sensitive toward

structural changes. Although the oxidation of the methyl

group to the hydroxymethyl analogue 140 only was accom-

panied by a minor decrease in cellular activity, the pharma-

cological activity in the Ghosh Schild rat was reduced

significantly (140, entry 3 vs 4, entry 1). An even more

pronounced decrease in both in vitro and in vivo efficacy

was observed for the ether derivative 142 (entry 4 vs entry 1).

On the other hand, the replacement of the methyl group by a

cyclopropyl substituent was well-tolerated and resulted in a

low ED₅₀value of 0.1 μmol/kg in the Ghosh Schild rat (139,

entry 2 vs 4, entry 1). The data reported in Table 4 also

suggests that the imidazole substitution pattern exerts little

influence on hERG binding. The three target compounds 139,

140, and 142 did not cause any noteworthy hERG inhibition

at a dose of 10 μM. This is an interesting finding because the

3658 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

Table 6. Titration Curves of Selected 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazoles in the Ghosh Schild Rat (x Axis: Time [0-300 min]; y Axis: Acid

Output [0-30 μmol/15 min])

replacement of the methyl group against the cyclopropyl

moiety was accompanied by an increase in lipophilicity

(logD of 4: 2.52 vs logD of 139: 2.84). Whereas in the case

of the carboxamide residue lipophilicity constituted an im-

portant parameter for hERG binding, this might not be the

case for the substituents attached to the imidazole ring.

The replacement of the imidazole N-substituent against a

hydrogen atom resulted in an increased affinity toward the

H^þ/K^þ-ATPase and a slight decrease in cellular activity and

efficacy in the rat (150, entry 5 vs 4, entry 1). Interestingly,

this modification was accompanied by an increase in lipo-

philicity (logD of 150: 2.82 vs logD of 4: 2.52) and a decrease

in hERG-binding.

3.5. Influence of the Substitution Pattern on the Basicity of

the Target Compounds. The pK_avalues of 30 target com-

pounds were determined by potentiometric titration in 0.15

mol/L KCl solutions in the range of pH 2.0-11.0 at 25 °C

using methanol as cosolvent. The following conclusions can be

drawn from the values reported in Tables 1, 3, and 4: (a) The

tetrahydrochromenoimidazole scaffold is very well-suited for

the design of weakly basic P-CABs. Most of the target

compounds 2 possess pK_avalues in the range of 5.6-5.7, i.e.,

they are significantly less basic than the isomeric 7H-8,9-

dihydropyrano[2,3-c]imidazo[1,2-a]pyridines 1 (ΔpK_a∼ 1.3).⁵

(b) In general, the character of the carboxamide substituent

exerts little influence on the pK_avalue of the respective target

compound. The difluoroazetidine moiety constitutes an ex-

ception to this rule, and the introduction of this residue resulted

in a P-CAB with reduced basicity (10, Table 1, entry 4, pK_a=

5.36). A greater impact on the basicity was observed when the

typical carboxamide residue R5 was replaced by other struc-

tural motifs. The 1,3,4-oxadiazole substituted target com-

pound 42 (Table 1, entry 35) possesses a lower pK_avalue of

5.17, whereas the ether derivative 43 (Table 1, entry 36, pK_a=

6.24) is significantly more basic than the carboxamides listed in

Table 1. (c) Likewise, little variation of the pK_avalue was

observed when the carboxamide residue was kept constant and

the aryl moiety was modified (Table 3). Target compounds

with halide atoms in the ortho-position (107 and 108, Table 3,

entries 7 and 8, pK_a= 5.55/5.45) or ortho- and para-positions

(117, Table 3, entry 22, pK_a= 5.36) of the phenyl ring show

somewhat reduced basicity. (d) The preliminary data reported

in Table 4 suggests that effective modulation of the basicity

might be feasible by modification of the substituent R3

attached to the imidazole ring. The 2-cyclopropyl-substituted

tetrahydrochromenoimidazole 139 (Table 4, entry 2, pK_a=

5.28) was found to be significantly less basic than its 2-methyl

analogue 4 (entry 1, pK_a= 5.68). (e) The influence of the

substituent attached to the nitrogen atom of the imidazole ring

on the basicity of the respective P-CAB has to be studied in

more detail.

3.6. Species Dependence of Pharmacological Activity

(Ghosh Schild Rat versus Fistula Dog). The antisecretory

properties of the 29 most promising target compounds

(based on the ED₅₀value determined in the Ghosh Schild

rat) were assessed in the fasted, pentagastrin-stimulated

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3659

fistula dog (Table 5). The pH-curve obtained for the candi-

date 4 clearly illustrates that the single oral administration of

this compound (9 μmol/kg) resulted in fast and strong

inhibition of acid output and thus to a pronounced elevation

of intragastric pH up to almost neutrality. The lag phase

between the oral administration of tetrahydrochromenoimi-

dazole 4 and the onset of the pH-elevating effects is mostly

due to a delayed gastric emptying of residual acid.¹³In both

species, P-CAB 4 showed good oral bioavailability (rat:

64%, dog: 72%) and moderate clearance (rat: 1.26 L/h/kg,

dog: 0.28 L/h/kg).

the Ghosh Schild rat could have very different inhibition

profiles, one being a rapidly inversed inhibition whereas the

other is more protracted, with inhibition of the pentagastrin

response lasting for a considerable time. Against this back-

ground, the comparison of titration curves of selected

3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles in the Ghosh

Schild rat is of interest (Table 6, the same compounds were

selected as in Table 5). As mentioned above, the experiments

were conducted over a period of 300 min. Acid secretion was

stimulated by iv administration of pentagastrin from t = 30

min to t = 300 min. Different doses of each P-CAB were

administered after t = 90 min (2-8 rats/dose). At the highest

dose investigated in the Ghosh Schild rat (1.0 μmol/kg), the

maximum inhibition of acid output was achieved 60-90 min

after administration of the respective P-CAB (x axis:

150-180 min, compound 115 was not examined at a dose

of 1.0 μmol/kg). In most cases, the maximum inhibition of

acid output was maintained until the end of the experiment

(x-axis: 300 min). For compounds 13 and 27, a distinct

increase in acid output was observed in the period of

240-300 min, suggesting a more rapidly reversed inhibition

in these cases. However, most of the investigated compounds

showed a reasonable duration of action in the Ghosh Schild

rat and the observed species differences cannot be attributed

merely to different inhibition profiles. The 4-chloro-deriva-

tive 113, for example, showed a long duration of action in the

Ghosh Schild rat (Table 6) but only a short-lasting effect in

the fistula dog (Table 5). The mode of administration is

another difference between the two models (intraduodenally

in the rat, orally in the dog). If any of the compounds was

acid-sensitive, then some or most of the test compound might

be degraded even before it gets to the gut for absorption. To

this end, the stability of two of the target compounds shown

in Table 5 in 0.1 N hydrochloric acid was examined at 37 °C

over a period of 24 h. The P-CABs 4 and 11 were found to be

acid-stable and, based on their chemical structure, it is

reasonable to believe that neither of the other target com-

pounds shown in Figure 5 is acid-sensitive.

The acquired in vitro eADME data (microsomal clea-

rance) suggest that the species differences in efficacy cannot

be explained by significant differences in stability of the

parent compounds in the dog/rat. Kinetic investigations,

i.e., the determination of the concentration of the respective

P-CAB in the serum of the dog, have not yet been conducted

for a satisfactory number of 3,6,7,8-tetrahydrochromeno-

[7,8-d]imidazoles. The result of such experiments might help

to explain the pronounced species dependence of pharma-

cological activity observed in this structural class. Differ-

ences in the amino acid sequence and the 3D structure

between the gastric proton pump of the dog and the H^þ/

K^þ-ATPase of the rat might also account for these findings.

In conclusion, although doses of 9 μmol/kg of several

target compounds (e.g., the azetidines 8, 10, and 11, the

ethylcarboxamide 22, the cyclopropylcarboxamide 25, and

the 4-chloro-2-methyl derivatives 129, 130, and 131, some

pH-metry curves are not depicted in Table 5) were able to

increase the intragastric pH to a value >5 for at least 5 h,

none of the investigated 3,6,7,8-tetrahydrochromeno[7,8-

d]imidazoles was more potent than the candidate 4.

The study of further 3,6,7,8-tetrahydrochromeno[7,8-

d]imidazoles in the fistula dog revealed that the pharmaco-

logical activity of the respective compound in the dog could

not be predicted from its antisecretory activity in the Ghosh

Schild rat. Whereas for some compounds (like 4) the low

ED₅₀value (0.23 μmol/kg) determined in the Ghosh Schild

rat was reflected in a long lasting increase of the intragastric

pH in the fistula dog (pH-elevation to >5 for ∼8 h), other

3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles were signifi-

cantly more active in the Ghosh Schild rat than in the fistula

dog. For instance, the introduction of a chloro atom into the

2-methylphenyl substituent resulted in an increase of the

pharmacological activity in the Ghosh Schild rat (115:

ED₅₀= 0.1 μmol/kg versus 4:ED₅₀= 0.23 μmol/kg). However,

the increase of the intragastric pH caused by target compound

115 (Ar = 4-chloro-2-methylphenyl) was of shorter duration

(pH-elevation to >5 for ∼4 h versus ∼8 h). The same trend was

visible in the case of the 4-chlorophenyl derivative 113 (Ghosh

Schild rat: ED₅₀= 0.15 μmol/kg, fistula dog: pH-elevation to

>5 for ∼2 h). The species difference was even more pronounced

for some analogues of 4 that showed a potent antisecretory

activity in the Ghosh Schild rat (ED₅₀< 0.5 μmol/kg) but

did not cause any significant pH elevation in the dog, e.g., the

5-(2-oxopropylcarboxamide) 27, the 8-(2-ethylphenyl) deriva-

tive 109, or the 3-cyclopropyl analogue 139. The comparison of

the carboxamides 11 and 13 illustrates that small structural

changes that are readily tolerated in the Ghosh Schild rat can

exert a strong influence on the pharmacological activity in the

dog. Comparable ED₅₀values of 0.3 and 0.4 μmol/kg were

determined for both alkoxyazetidines 11 (3-methoxy) and 13

(3-propoxy) in the rat. In the case of the methoxy derivative 11,

the recorded pH-metry curve was similar to the one of the

candidate 4, with an increase in pH to a value >5 for 6-8 h. In

contrast, administration of the propoxy derivative 13 did not

cause a noteworthy rise of the intragastric pH. The analysis of

the pH curves obtained for the methylcarboxamides 21 and 129

in comparison to their dimethyl analogues 4 and 115 also

indicates that the SAR in the fistula dog is distinct and different

to the one observed for the Ghosh Schild rat. Whereas the

removal of one methyl group from the dimethylcarboxamide

residue present in 4 exerted little influence on the pharmaco-

logical activity in the rat (4 and 21: ED₅₀values of 0.23 and

0.25 μmol/kg), a significant difference in the duration of pH

elevation was observed in the fistula dog (4:pH>5for8hvs21:

2.5 h). Also in the 4-chloro-2-methylphenyl series, comparable

ED₅₀values of 0.1 and 0.15 μmol/kg were determined for both

analogues 115 and 129 in the Ghosh Schild rat. Interestingly, in

this series, the methylcarboxamide caused a much more potent

rise of the intragastric pH than the dimethylcarboxamide

(129: pH > 5 for 8 h vs 115: 4 h).

4. Summary

Methodological differences between the two models might

partly account for the differences observed in SAR. For

example, two compounds with a comparable ED₅₀value in

In conclusion, 65 enantiopure tetrahydrochromenoimida-

zoles were prepared either by hydrolysis of the readily available

3660 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

candidate 4 or by Noyori asymmetric reduction of the respec-

tive ketone precursors and Mitsunobu cyclization of the

resulting diols. A clear SAR was established with respect to

the in vitro activity of the target compounds, their antisecre-

tory properties in the Ghosh Schild rat, and their affinity

toward the hERG channel. In the case of the carboxamide

residue, small aliphatic groups and cycloaliphatic rings were

found to be most beneficial. Within each series, an increase in

lipophilicity resulted in enhanced hERG binding. Regarding

the phenyl residue, ortho-/para-substitution or ortho-/para-

disubstitution witha methylgroupor chloro and fluoro atoms

turned out to be most favorable. The presence of a para-chloro

atom strongly enhanced both the pharmacological activity of

the target compound in the Ghosh Schild rat and its affinity

toward the hERG channel. For the most promising target

compounds, efficacy and duration of the antisecretory effect

was assessed by 24 h pH-metry in the fistula dog and,

surprisingly, a different SAR was observed. Further investi-

gations related to the bioavailability of the target compounds

in the dog and the structural differences between the gastric

proton pump enzyme expressed in both species will offer

possible explanations for this finding. Several target com-

pounds possess a profile comparable to the one of the tetra-

hydrochromenoimidazole 4 and constitute promising candi-

dates for further development as drugs for the treatment of

acid-related diseases.

>95% (see Supporting Information). High resolution mass

spectra were obtained on an Agilent MSD-TOF instrument

using electrospray ionization (ESI positive).

5.1.2. Conversion of 3,6,7,8-Tetrahydrochromeno[7,8-d]imida-

zole-5-carboxamides into Carboxylic Acids. General Procedure

1 (Reduction of Carboxamides to Alcohols with Lithium

Triethylborohydride). At a temperature of 0 °C, lithium triethyl-

borohydride (1 M solution in THF, 3.5 equiv) was slowly added to

a suspension of the respective carboxamide in THF (final substrate

concentration ∼0.15 M). The yellow solution was stirred for 2 h at

room temperature. Water (∼100 mL/mol carboxamide) and so-

dium hydroxide (330 g/mol carboxamide) was added to the

reaction mixture, and stirring was continued for 20 min. A solution

of hydrogen peroxide in water (30 wt %, ∼1 L/mol carboxamide)

was added slowly and with caution. The biphasic mixture was

stirred at room temperature. Dichloromethane and water was

added, and the phases were separated. The aqueous phase was

extracted with dichloromethane (2ꢀ). The combined organic

phases were dried over magnesium sulfate, and the solvent was

evaporated. The crude title compound was used for the subsequent

oxidation step without further purification.

[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazol-5-yl]methanol (5). Preparation from

carboxamide 4 (16.1 g, 44.4 mmol) and lithium triethylborohy-

dride (1 M solution in THF, 155 mL, 155 mmol) according to

general procedure 1. Yield: >100% (crude product, 16.6 g of a

yellow solid). ¹H NMR (DMSO-d₆, 300 MHz): δ = 1.98 (m_c, 1

H), 2.20 (m_c, 1 H), 2.38 (s, 3 H), 2.45 (s, 3 H), 2.89 (m_c, 2 H), 3.66

(s, 3 H), 4.55 (m_c, 2 H), 5.04 (t, 1 H), 5.22 (dd, 1 H), 7.05 (s, 1 H),

7.26 (m_c, 3 H), 7.48 (m_c, 1 H). HRMS calcd for C₂₀H₂₃N₂O₂m/z

(MH^þ), 323.1754; found, 323.1755.

5. Experimental Section

[(8S)-8-(4-Chlorophenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazol-5-yl]methanol (121). Preparation from car-

boxamide 113 (9.7 g, 25.3 mmol) and lithium triethylborohy-

dride (1 M solution in THF, 91 mL, 91 mmol) according to

general procedure 1. Yield: 35% (crude product, 3.0 g). The

aqueous phase was filtered over a pad of silica gel. The silica gel

was extracted with a mixture of dichloromethane (600 mL) and

methanol (300 mL). Evaporation of the solvent furnished an-

other batch of the title compound (5.2 g, 60% yield). ¹H NMR

(DMSO-d₆, 300 MHz): δ = 2.04 (m_c, 1 H), 2.26 (m_c, 1 H), 2.46

(s, 3 H), 2.71 (m_c, 1 H), 2.87 (m_c, 1 H), 3.67 (s, 3 H), 4.53 (d, 2 H),

5.02 (t, 1 H), 5.16 (dd, 1 H), 7.04 (s, 1 H), 7.49 (m_c, 4 H).

[(8S)-8-(4-Chloro-2-methylphenyl)-2,3-dimethyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazol-5-yl]methanol (122). Preparation

from carboxamide 115 (8.4 g, <21.1 mmol) and lithium triethyl-

borohydride (1 M solution in THF, 64 mL, 64 mmol) according

to general procedure 1. Yield: 72% (crude product, 5.4 g of a

beige solid). ¹H NMR (DMSO-d₆, 300 MHz): δ = 1.95 (m_c, 1

H), 2.25 (m_c, 1 H), 2.38 (s, 3 H), 2.45 (s, 3 H), 2.91 (m_c, 2 H), 3.67

(s, 3 H), 4.56 (bs, 2 H), 5.04 (bt, 1 H), 5.22 (d, 1 H), 7.05 (s, 1 H),

7.33 (m_c, 2 H), 7.49-7.65 (m, 1 H). HRMS calcd for

C₂₀H₂₂ClN₂O₂m/z (MH^þ), 357.1364; found, 357.1365.

General Procedure 2 (Oxidation of Alcohols to Aldehydes

under Parikh-Doering Conditions).²⁷Sulfur trioxide pyridine

complex (∼3.0 equiv) was added portionwise to a suspension of

the respective alcohol in DMSO/triethylamine = 3:2 (v/v),

substrate concentration ∼0.20 M. The reaction mixture was

stirred for 3-17 h at room temperature, and water was added.

The title compound was isolated by filtration and dried in

vacuo.

5.1. Chemistry. 5.1.1. General. All chemicals were purchased

from the major chemical suppliers as highest purity grade and

used without any further purification. The hydrogenation cat-

alyst RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN] 82 was purchased

from Johnson Matthey, Cambridge, UK. The progress of the

reaction was monitored on Macherey-Nagel HPTLC plates

Nano-SIL 20 UV₂₅₄(0.20 mm layer, nano silica gel 60 with

fluorescence indicator UV₂₅₄) using dichloromethane/methanol

as solvent system. Column chromatography was performed

with Merck silica gel 60 (70-230 mesh ASTM) with the solvent

mixtures specified in the corresponding experiment. Spots were

visualized by iodine vapor or by irradiation with ultraviolet light

(254 nm). Melting points (mp) were taken in open capillaries

€

on a Buchi B-540 melting point apparatus and are uncorrected.

¹H NMR spectra were recorded with Bruker FT-NMR spectro-

meters (DRX 200, AX 300, AV 400) at frequencies of 200, 300,

or 400 MHz, respectively. CDCl₃or DMSO-d₆were used as

solvents. The chemical shifts were reported as parts per million

(δ ppm) with tetramethylsilane (TMS) as an internal standard.

Elemental analysis was performed on a Carlo Erba 1106 C, H, N

analyzer. The identity and the purity of all available title

compounds was verified by HPLC/HRMS. High pressure liquid

chromatography was performed under the following experi-

mental conditions: Instrument: Agilent Technologies, 1200

series. Column: Agilent Extend C18 column 50 mm ꢀ 4.6 mm,

1.8 μm. Eluant for title compounds 8, 9, 11, 12, 14-20, 22-24,

26, 27, 29, 32-35: A, water/acetonitrile = 95:5 (v/v) þ 0.1% of

formic acid; B, acetonitrile. Eluant for title compounds 21, 25,

28, 30, 36-40, 42, 43, 105-120, 127-131, 139, 142, 150: A,

water/acetonitrile = 90:10 (v/v) þ 0.05% of formic acid, B,

acetonitrile/water = 95:5 (v/v) þ 0.05% of formic acid. Gra-

dient: A/B: 100:0 (0-0.1 min), 100:0 to 0:100 (0.1-4 min), 0:100

to 100:0 (4-5 min), 100:0 (5-6 min). Flow rate: 1.0 mL/min

(title compounds 8, 9, 11, 12, 14-20, 22-24, 26, 27, 29, 32-35),

1.2 mL/min (title compounds 21, 25, 28, 30, 36-40, 42, 43,

105-120, 127-131, 139, 142, 150). Temp: 50 °C. Detection:

DAD at 220 nm. All target compounds with the exception of

P-CABs 119 (90.8%) and 139 (94.1%) possessed a purity of

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazole-5-carbaldehyde (6). Prepared by reduction

of carboxamide 4 with lithium aluminum hydride: Lithium alu-

minum hydride (20 mg, 0.54 mmol) was added to a suspension of

carboxamide 4 (300 mg, 0.83 mmol) in THF (5 mL). The

reaction mixture was stirred for 1 h at room temperature and

quenched by addition of water (20 μL), 4 N sodium hydroxide

solution (20 μL), and more water (60 μL). The organic phase was

dried over sodium sulfate, and the solvent was evaporated. The

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3661

residue (190 mg of a colorless foam) was purified by column

chromatography (30 g of silica gel, eluant: dichloromethane).

Evaporation of the corresponding fractions afforded the title

compound in 46% yield (120 mg of a colorless foam). Prepared

by oxidation of alcohol 5 with Dess Martin Periodinane: A

solution of alcohol 5 (300 mg, 0.93 mmol) in dichloromethane

(8 mL) was added to a solution of Dess-Martin periodinane

(430 mg, 1.01 mmol) in dichloromethane (8 mL). After a

reaction time of 2 h at room temperature, 1 N sodium hydroxide

solution (10 mL) was added and stirring was continued for 10

min. The phases were separated. The organic phase was washed

with 1.5 M sodium hydroxide solution (2ꢀ). The aqueous phase

was extracted with dichloromethane (1ꢀ). The combined

organic phases were dried over sodium sulfate, and the solvent

was evaporated. The residue was purified by column chromato-

graphy [30 g of silica gel, eluant: dichloromethane/methanol =

100:1 (v/v)]. Evaporation of the corresponding fractions af-

forded the title compound (140 mg of a colorless solid, 49%

yield). Prepared by Parikh-Doering oxidation of alcohol 5:

Preparation from alcohol 5 (8.0 g, 24.8 mmol) and sulfur

trioxide pyridine complex (12.8 g, 80.4 mmol) according to

general procedure 2. Yield: 78% (6.2 g of a brown solid); mp

for 2 d. The reaction mixture was cooled to room temperature,

transferred into a 20 L vessel, and treated with concentrated

hydrochloric acid (adjustment of a pH value of 4-5, approxi-

mately 210 mL) and water (9 L). The colorless suspension was

stirred for 3 h at room temperature. The title compound (67.0 g

of a colorless solid, 80% yield) was isolated by filtration; mp

>285 °C (decomp). ¹H NMR (DMSO-d₆, 300 MHz): δ = 1.93

(m_c, 1 H), 2.25 (m_c, 1 H), 2.39 (s, 3 H), 2.50 (s), 3.24 (m_c, 2 H),

3.72 (s, 3 H), 5.30 (dd, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H), 7.64 (s,

1 H), 12.56 (bs, 1 H). HRMS calcd for C₂₀H₂₁N₂O₃m/z (MH^þ),

337.1547; found, 337.1538.

(8S)-8-(4-Chlorophenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazole-5-carboxylic Acid (125). Oxidation of

aldehyde 123 (6.1 g, 17.9 mmol) according to general procedure

3. Yield: 97% (6.18 g of a colorless solid); mp 348 °C (decomp).

¹H NMR (DMSO-d₆, 300 MHz): δ = 2.00 (m_c, 1 H), 2.26 (m_c, 1

H), 2.50 (s), 3.16 (m_c, 2 H), 3.72 (s, 3 H), 5.23 (dd, 1 H), 7.49 (m_c,

4 H), 7.63 (s, 1 H).

(8S)-8-(4-Chloro-2-methylphenyl)-2,3-dimethyl-3,6,7,8-tetra-

hydrochromeno[7,8-d]imidazole-5-carboxylic Acid (126). Oxida-

tion of aldehyde 124 (3.2 g, 9.0 mmol) according to general

procedure 3. Yield: >100% (3.61 g of a colorless solid, presum-

ably due to the presence of inorganic salts). ¹H NMR (DMSO-d₆,

300 MHz): δ = 1.92 (m_c, 1 H), 2.26 (m_c, 1 H), 2.40 (s, 3 H), 2.50

(s), 3.23 (m_c, 2 H), 3.72 (s, 3 H), 5.30 (d, 1 H), 7.32 (m_c, 2 H), 7.50

(m_c, 1 H), 7.62 (s, 1 H). HRMS calcd for C₂₀H₂₀ClN₂O₃m/z

(MH^þ), 371.1157; found, 371.1153.

1

216-220 °C. H NMR (DMSO-d₆, 300 MHz): δ = 1.98 (m_c,

1 H), 2.29 (m_c, 1 H), 2.39 (s, 3 H), 2.54 (s, 3 H), 3.34 (m_c, 2 H),

3.77 (s, 3 H), 5.32 (dd, 1 H), 7.27 (m_c, 3 H), 7.48 (m_c, 1 H), 7.69

(m_c, 1 H), 10.17 (s, 1 H). HRMS calcd for C₂₀H₂₁N₂O₂m/z

(MH^þ), 321.1598; found, 321.1598.

(8S)-8-(4-Chlorophenyl)-2,3-dimethyl-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazole-5-carbaldehyde (123). Preparation from

alcohol 121 (5.1 g, 14.9 mmol) and sulfur trioxide pyridine

complex (7.1 g, 44.6 mmol) according to general procedure 2.

Yield: 96% (4.86 g of a colorless solid); mp 260-262 °C. H

NMR (DMSO-d₆, 300 MHz): δ = 2.04 (m_c, 1 H), 2.30 (m_c, 1 H),

2.54 (s, 3 H), 3.26 (m_c, 2 H), 3.78 (s, 3 H), 5.25 (dd, 1 H), 7.50 (m_c,

4 H), 7.70 (s, 1 H), 10.14 (s, 1 H).

5.1.3. Conversion of 3,6,7,8-Tetrahydrochromeno[7,8-d]imida-

zole-5-carboxylic Acids into Carboxamides. General Procedure

4 (Conversion of Carboxylic Acids into Carboxamides Using

EDC-HCl). N-(3-Dimethylaminopropyl)-N⁰-ethylcarbodiimide

hydrochloride (EDC-HCl, 1.3-2.0 equiv) and a catalytic

amount of 4-(dimethylamino)pyridine (DMAP) was added to

a suspension of the corresponding carboxylic acid in dichloro-

methane (10-15 mL). Stirring at room temperature afforded a

solution, which was treated with the corresponding amine

(1.0-3.0 equiv) or the hydrochloride salt of the corresponding

amine (1.0-3.0 equiv) and triethylamine (1.1-6 equiv). After a

period of 0.5-18 h at room temperature, the corresponding title

compound was isolated as described in workup procedure 1.

General Procedure 5 (Conversion of Carboxylic Acids into

Carboxamides Using TBTU). N,N-Diisopropylethylamine

(DIPEA, 2.5 equiv) was added to a suspension of the corre-

sponding carboxylic acid and O-benzotriazol-1-yl-N,N,N⁰,N⁰-

tetramethyluronium tetrafluoroborate (TBTU, 1.5 equiv) in

DMF. After heating at 40 °C for 0.5-1 h, a solution was

obtained. After addition of the corresponding amine or the

hydrochloride salt of the corresponding amine (1.3-3.0 equiv),

the reaction mixture was heated at 40 °C for 1-2 h or stirred at

room temperature for 17 h and the corresponding title com-

pound was isolated as described in workup procedure 1 or 2.

General Procedure 6 (Conversion of Carboxylic Acids into

Carboxamides Using CDI). A solution of the corresponding

carboxylic acid and 1,1⁰-carbonyldiimidazole (CDI, 2.0 equiv)

in dichloromethane was stirred for 1-1.5 h at room tempera-

ture. The corresponding amine (2.0 equiv) and a drop of acetic

acid was added and stirring was continued for 4-17 h at room

temperature. The corresponding title compound was isolated as

described in workup procedure 3.

1

(8S)-8-(4-Chloro-2-methylphenyl)-2,3-dimethyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carbaldehyde (124). Preparation

from alcohol 122 (5.3 g, 14.9 mmol) and sulfur trioxide pyridine

complex (7.1 g, 44.6 mmol) according to general procedure 2.

Yield: 28% (1.43 g of a colorless solid). After a period of 3 days,

a second batch of the title compound (1.82 g, 34% yield) was

isolated by filtration of the mother liquor and washing of the

precipitate with water (20 mL); mp 170-172 °C. ¹H NMR

(DMSO-d₆, 300 MHz): δ = 1.97 (m_c, 1 H), 2.29 (m_c, 1 H),

2.39 (s, 3 H), 2.53 (s, 3 H), 3.32 (m_c), 3.78 (s, 3 H), 5.31 (d, 1 H),

7.34 (m_c, 2 H), 7.49 (m_c, 1 H), 7.71 (s, 1 H), 10.17 (s, 1 H). HRMS

calcd for C₂₀H₂₀ClN₂O₂m/z (MH^þ), 355.1208; found,

355.1210.

General Procedure 3 (Oxidation of Aldehydes to Carboxylic

Acids under Kraus Conditions).²⁸A solution of sodium chlorite

(1.3-1.7 equiv) and sodium dihydrogen phosphate monohy-

drate (1.2-2.0 equiv) in water was added to a suspension of the

respective aldehyde in tert-butanol and 2-methyl-2-butene [final

substrate concentration ∼0.15 M, ratio of water/tert-butanol/2-

methyl-2-butene = 15:45:40 (v/v/v)]. After a period of 5-20 h at

40-45 °C, the reaction mixture was diluted with water. Stirring

was continued for several minutes, and the title compound was

isolated by filtration.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazole-5-carboxylic Acid (7). Prepared by oxida-

tion of aldehyde 6: Oxidation of aldehyde 6 (6.1 g, 19.1 mmol)

according to general procedure 3. Yield: 91% (5.8 g of a color-

General Procedure 7 (Conversion of Carboxylic Acids into

Carboxamides Using TBTU). The corresponding amine or the

hydrochloride salt of the corresponding amine (2.0 equiv) was

added to a solution of the corresponding carboxylic acid

(200 mg), N,N-diisopropylethylamine (DIPEA, 2.5 equiv), and

O-benzotriazol-1-yl-N,N,N⁰,N⁰-tetramethyluronium tetrafluoro-

borate (TBTU, 1.5 equiv) in DMF (5 mL). The reaction mixture

was stirred at room temperature for 2 h, and the corresponding

title compound was isolated as described in workup procedure 2.

Workup Procedure 1 (Isolation of Carboxamides). After addi-

tion of water, the phases were separated. The organic phase was

1

less solid); mp 297-299 °C. H NMR (DMSO-d₆, 300 MHz):

δ = 1.93 (m_c, 1 H), 2.26 (m_c, 1 H), 2.39 (s, 3 H), 2.51 (s), 3.24 (m_c,

2 H), 3.72 (s, 3 H), 5.30 (dd, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H),

7.64 (s, 1 H), 12.55 (bs, 1 H). Prepared by hydrolysis of

carboxamide 4: Carboxamide 4 (90.0 g, 0.25 mol) and anhydrous

sodium hydroxide beads (100 g, 2.5 mol) were dissolved in

ethylene glycol (900 mL). In a three-neck flask equipped with

a distillation bridge, the reaction mixture was heated at 195 °C

3662 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

washed with sodium bicarbonate solution (1-2ꢀ) and water

(1ꢀ). The combined aqueous phases were extracted with di-

chloromethane (1-2ꢀ). The combined organic phases were

dried over magnesium sulfate or sodium sulfate, the solvent

was evaporated, and the crude product was purified by column

chromatography.

Workup Procedure 2 (Isolation of Carboxamides). The reac-

tion mixture was poured on a mixture of dichloromethane and

water. The phases were separated and the aqueous phase was

extracted with dichloromethane (2ꢀ). The combined organic

phases were washed with water, dried over sodium sulfate, and

the solvent was evaporated. The crude product was purified by

column chromatography on silica gel and crystallization/wash-

ing. The solvents employed for column chromatography, crys-

tallization, and washing are specified in the corresponding

experiments.

Workup Procedure 3 (Isolation of Carboxamides). The reac-

tion mixture was poured on water and a pH-value of 8 was

adjusted by addition of saturated sodium bicarbonate solution.

The aqueous phase was extracted with dichloromethane (2ꢀ).

The combined organic phases were evaporated to dryness. The

title compound was purified by column chromatography on

silica gel and crystallization/washing. The solvents employed for

column chromatography, crystallization, and washing are spe-

cified in the corresponding experiments.

2.79 (m_c, 1 H), 3.03 (m_c, 1 H), 3.21 (d, 3 H), 3.70, 3.83 (s, m_c, 5 H),

4.10, 4.22 (m_c, bs, 3 H), 5.31 (d, 1 H), 7.05 (s, 1 H), 7.26 (m_c,3H),7.46

(m_c, 1 H). HRMS calcd for C₂₄H₂₈N₃O₃m/z (MH^þ), 406.2125;

found, 406.2127. Anal. (C₂₄H₂₇N₃O₃): C, H, N.

(8S)-5-[(3-Ethoxyazetidin-1-yl)carbonyl]-2,3-dimethyl-8-(2-

methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (12).

Preparation from carboxylic acid 7 (500 mg, 1.5 mmol) and

3-ethoxyazetidine (303 mg, 3.00 mmol) according to general

procedure 5/workup procedure 2. Eluant for column chroma-

tography: first column, dichloromethane/methanol = 20:1 (v/

v); second column, ethyl acetate/methanol = 9:1 (v/v). Yield:

1

43% (270 mg of a colorless foam). H NMR (DMSO-d₆, 300

MHz): δ = 1.13 (m_c, 3 H), 1.95 (m_c, 1 H), 2.22 (m_c, 1 H), 2.38 (s,

3 H), 2.47 (s, 3 H), 2.80 (m_c, 1 H), 3.04 (m_c, 1 H), 3.40 (m_c, 2 H),

3.70, 3.68-4.31 (s, m_c, 8 H), 5.31 (d, 1 H), 7.06 (s, 1 H), 7.26 (m_c,

3 H), 7.46 (m_c, 1 H). HRMS calcd for C₂₅H₃₀N₃O₃m/z (MH^þ),

420.2282; found, 420.2290.

(8S)-5-[(3-Propoxyazetidin-1-yl)carbonyl]-2,3-dimethyl-8-(2-

methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (13).

Preparation from carboxylic acid 7 (0.5 g, 1.5 mmol) and

3-propoxyazetidine (346 mg, 3.00 mmol) according to general

procedure 5/workup procedure 2. Eluant for column chroma-

tography: dichloromethane/methanol = 20:1 (v/v). Solvent for

crystallization: ethyl acetate (1 mL)/diethyl ether (10 mL).

1

Yield: 40% (260 mg of a colorless solid). H NMR (DMSO-

d₆, 300 MHz): δ = 0.87 (m_c, 3 H), 1.51 (m_c, 2 H), 1.95 (m_c, 1 H),

2.20 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.80 (m_c, 1 H), 3.02 (m_c,

1 H), 3.29 (m_c), 3.70, 3.82, 3.93, 4.02, 4.18, 4.28 (s, 5 m_c, 8 H),

5.31 (d, 1 H), 7.06 (s, 1 H), 7.26 (m_c, 3 H), 7.46 (m_c, 1 H).

(8S)-5-[(3-Hydroxyazetidin-1-yl)carbonyl]-2,3-dimethyl-8-(2-

methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (14).

Preparation from carboxylic acid 7 (0.5 g, 1.5 mmol) and

3-hydroxyazetidine hydrochloride (312 mg, 2.86 mmol) according

to general procedure 5/workup procedure 2. Eluant for column

chromatography: dichloromethane/methanol = 20:1 (v/v). Solvent

for washing: acetone (0.5 mL)/diethyl ether (10 mL). Yield: 58%

(340 mg of a colorless solid); mp 303 °C. ¹H NMR (DMSO-d₆, 300

MHz): δ=1.96(m_c, 1H), 2.21(m_c, 1H), 2.38(s, 3H), 2.47 (s, 3 H),

2.80 (m_c, 1H), 3.03(m_c, 1 H), 3.69, 3.73 (s, m_c, 5 H), 4.01, 4.20 (2 m_c,

2 H), 4.49 (m_c, 1 H), 5.32 (d, 1 H), 5.71 (t, 1 H), 7.02 (s, 1 H), 7.26

(m_c, 3 H), 7.46 (m_c, 1 H). HRMS calcd for C₂₃H₂₆N₃O₃m/z

(MH^þ), 392.1969; found, 392.1969. Anal. (C₂₃H₂₅N₃O₃): C, H, N.

1-{[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazol-5-yl]carbonyl}-azetidin-3-ylmethanol (15).

Preparation from carboxylic acid 7 (0.5 g, 1.5 mmol) and

azetidin-3-ylmethanol (synthesis described in the Supporting

Information, 260 mg, 2.97 mmol) according to general proce-

dure 6/workup procedure 3. Eluant for column chromato-

graphy: toluene/dioxane/methanol = 60:35:5 (v/v/v). Solvent

for crystallization: ethyl acetate/n-heptane. Yield: 58% (350 mg

of colorless crystals); mp 222-225 °C. ¹H NMR (DMSO-d₆, 300

MHz): δ = 1.97 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s, 3

H), 2.68 (m_c, 1 H), 2.81 (m_c, 1 H), 3.03 (m_c, 1 H), 3.53 (m_c, 3 H),

3.70, 3.70-4.07 (s, m, 6 H), 4.79 (m_c, 1 H), 5.31 (d, 1 H), 7.03 (s, 1

H), 7.27 (m_c, 3 H), 7.48 (m_c, 1 H). HRMS calcd for C₂₄H₂₈N₃O₃

m/z (MH^þ), 406.2125; found, 406.2126.

1-{[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazol-5-yl]carbonyl}-3-methylazetidin-3-ol (16).

Preparation from carboxylic acid 7 (0.75 g, 2.2 mmol) and

3-methylazetidin-3-ol (synthesis described in the Supporting

Information, 400 mg, 4.44 mmol) according to general proce-

dure 6/workup procedure 3. Eluant for column chromatogra-

phy: toluene/dioxane/methanol/triethylamine = 60:34:5:1 (v/v/

v/v). Solvent for crystallization: ethyl acetate/n-heptane. Yield:

66% (590 mg of colorless crystals); mp 279-282 °C. ¹H NMR

(DMSO-d₆, 300 MHz): δ = 1.40 (d, 3 H), 1.99 (m_c, 1 H), 2.23

(m_c, 1 H), 2.39 (s, 3 H), 2.47 (s, 3 H), 2.81 (m_c, 1 H), 3.04 (m_c, 1

H), 3.69 (s, m_c, 4 H), 3.86 (m_c, 3 H), 5.32 (d, 1 H), 5.64 (d, 1 H),

7.02 (s, 1 H), 7.25 (m_c, 3 H), 7.46 (m_c, 1 H). HRMS calcd for

C₂₄H₂₈N₃O₃m/z (MH^þ), 406.2125; found, 406.2119.

(8S)-5-[(Azetidin-1-yl)carbonyl]-2,3-dimethyl-8-(2-methyl-

phenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (8). Pre-

paration from carboxylic acid 7 (1.0 g, 3.0 mmol) and azetidine

(290 μL, 4.23 mmol) according to general procedure 7/workup

procedure 1. Eluant for column chromatography: dichloro-

methane/methanol = 50:1 (v/v). Yield: 53% (600 mg of a

colorless solid); mp 177-178 °C. ¹H NMR (DMSO-d₆, 300

MHz): δ = 1.96 (m_c, 1 H), 2.22 (m_c, 3 H), 2.38 (s, 3 H), 2.47 (s, 3

H), 2.81 (m_c, 1 H), 3.04 (m_c, 1 H), 3.69 (s, 3 H), 3.87 (m_c, 1 H),

4.03 (m_c, 3 H), 5.31 (dd, 1 H), 7.03 (s, 1 H), 7.25 (m_c, 3 H), 7.46

(m_c, 1 H). HRMS calcd for C₂₃H₂₆N₃O₂m/z (MH^þ), 376.2020;

found, 376.2020.

(8S)-5-[(3-Fluoroazetidin-1-yl)carbonyl]-2,3-dimethyl-8-(2-

methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (9).

Preparation from carboxylic acid 7 (0.5 g, 1.5 mmol) and

3-fluoroazetidine hydrochloride (418 mg, 3.75 mmol) according

to general procedure 5/workup procedure 2. Eluant for column

chromatography: dichloromethane/methanol = 20:1 (v/v). Sol-

vent for washing: diethyl ether (10 mL)/acetone (0.5 mL). Yield:

1

76% (450 mg of a colorless solid); mp 130-132 °C. H NMR

(DMSO-d₆, 300 MHz): δ = 1.96 (m_c, 1 H), 2.22 (m_c, 1 H), 2.38 (s,

3 H), 2.47 (s), 2.85 (m_c, 1 H), 3.05 (m_c, 1 H), 3.70 (s, 3 H),

3.90-4.50 (m, 4 H), 5.32, 5.43 (d, bd, 2 H), 7.09 (s, 1 H), 7.25 (m_c, 3

H), 7.46 (m_c, 1 H). HRMS calcd for C₂₃H₂₅FN₃O₂m/z (MH^þ),

394.1925; found, 394.1933. Anal. (C₂₃H₂₄FN₃O₂): C, H, N.

(8S)-5-[(3,3-Difluoroazetidin-1-yl)carbonyl]-2,3-dimethyl-8-

(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (10).

Preparation from carboxylic acid 7 (0.5 g, 1.5 mmol) and

3,3-difluoroazetidine hydrochloride (388 mg, 3.00 mmol)

according to general procedure 5/workup procedure 2. Eluant

for column chromatography: dichloromethane/methanol =

20:1 (v/v). Solvent for washing: diisopropyl ether (5 mL)/diethyl

ether (5 mL)/petroleum ether (5 mL). Yield: 63% (390 mg of a

colorless solid); mp 202-203 °C. ¹H NMR (DMSO-d₆, 300

MHz): δ = 1.95 (m_c, 1 H), 2.22 (m_c, 1 H), 2.39 (s, 3 H), 2.48 (s,

3 H), 2.87 (m_c, 1 H), 3.09 (m_c, 1 H), 3.72 (s, 3 H), 4.46 (m_c, bs,

4 H), 5.32 (d, 1 H), 7.19 (s, 1 H), 7.25 (m_c, 3 H), 7.47 (m_c, 1 H).

(8S)-5-[(3-Methoxyazetidin-1-yl)carbonyl]-2,3-dimethyl-8-(2-

methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (11).

Preparation from carboxylic acid 7 (0.9 g, 2.7 mmol) and

3-methoxyazetidine hydrochloride (380 mg, 3.1 mmol) according to

general procedure 7/workup procedure 1. Eluant for column chro-

matography: dichloromethane/methanol = 50:1 (v/v). Yield: 57%

(650 mg of a colorless solid); mp 217 °C; ¹H NMR (DMSO-d₆, 300

MHz): δ = 1.97 (m_c, 1 H), 2.20 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s, 3 H),

Article

(8S)-5-[(3-Methoxy-3-methylazetidin-1-yl)carbonyl]-2,3-dime-

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3663

HRMS calcd for C₂₂H₂₆N₃O₂m/z (MH^þ), 364.2020; found,

364.2022.

thyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imida-

zole (17). Preparation from carboxylic acid 7 (0.75 g, 2.2 mmol)

and 3-methoxy-3-methylazetidine (synthesis described in the Sup-

porting Information, 450 mg, 4.44 mmol) according to general pro-

cedure 6/workup procedure 3. Eluant for column chromatography:

toluene/dioxane/methanol/triethylamine = 60:35:5:1 (v/v/v/v).

Solvent for crystallization: ethyl acetate/n-heptane. Yield: 28%

(260 mg of colorless crystals); mp207-208 °C. ¹H NMR (DMSO-

d₆, 300 MHz):δ=1.43(d, 3 H), 1.97(m_c, 1H), 2.22(m_c, 1H), 2.39

(s, 3 H), 2.47 (s, 3 H), 2.80 (m_c, 1 H), 3.04 (m_c, 1 H), 3.17 (d, 3 H),

3.70, 3.62-4.01 (s, m, 7 H), 5.32 (d, 1 H), 7.07 (s, 1 H), 7.26 (m_c,

3 H), 7.46 (m_c, 1 H). HRMS calcd for C₂₅H₃₀N₃O₃m/z (MH^þ),

420.2282; found, 420.2282. Anal. (C₂₅H₂₉N₃O₃): C, H, N.

1-{[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazol-5-yl]carbonyl}-N,N-dimethylazetidine-

3-carboxamide (18). Preparation from carboxylic acid 7 (0.5 g,

1.5 mmol) and N,N-dimethylazetidine-3-carboxamide (syn-

thesis described in the Supporting Information, 380 mg, 2.97

mmol) according to general procedure 6/workup procedure 3.

Eluant for column chromatography: first column, toluene/diox-

ane/methanol = 60:35:5 (v/v/v); second column, dichloro-

methane/methanol = 100:3 (v/v); third column, toluene/dio-

xane/methanol = 60:35:5 (v/v/v). Yield: 41% (268 mg of a color-

less solid); mp 100-105 °C. ¹H NMR (DMSO-d₆, 300 MHz): δ =

1.95 (m_c, 1 H), 2.23 (m_c, 1 H), 2.39 (s, 3 H), 2.47 (s, 3 H), 2.83, 2.83,

2.85 (s, m_c, s, 7 H), 3.70, 3.76 (s, m_c, 4 H), 4.06 (m_c, 4 H), 5.32 (dd, 1

H), 7.03 (s, 1 H), 7.26 (m_c, 3 H), 7.46 (m_c, 1 H). HRMS calcd for

C₂₆H₃₁N₄O₃m/z (MH^þ), 447.2391; found, 447.2394.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-propyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide (23). Preparation

from carboxylic acid 7 (0.50 g, 1.5 mmol) and propylamine

(247 μL, 3.0 mmol) according to general procedure 5/workup

procedure 2. Eluant for column chromatography: dichloro-

methane/methanol = 20:1 (v/v). Solvent for washing: diethyl

ether/petroleum ether. Yield: 88% (500 mg of a colorless solid);

mp 244 °C. ¹H NMR (DMSO-d₆, 300 MHz): δ = 0.92 (t, 3 H),

1.54 (m_c, 2 H), 1.93 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s,

3 H), 2.85 (m_c, 1 H), 3.10 (m_c, 1 H), (3.20, m_c, 2 H), 3.69 (s, 3 H),

5.28 (d, 1 H), 7.08 (s, 1 H), 7.25 (m_c, 3 H), 7.47 (m_c, 1 H), 8.15 (t, 1

H). HRMS calcd for C₂₃H₂₈N₃O₂m/z (MH^þ), 378.2176; found,

378.2175. Anal. (C₂₃H₂₇N₃O₂): H, N. For C: calcd, 73.18;

found, 72.34.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-(propan-2-yl)-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (24). Pre-

paration from carboxylic acid 7 (0.50 g, 1.5 mmol) and iso-

propylamine (257 μL, 3.0 mmol) according to general procedure

5/workup procedure 2. Eluant for column chromatography:

first column, dichloromethane/methanol = 50:1 (v/v); second

column, dichloromethane/methanol = 20:1 (v/v). Solvent for

washing: diethyl ether (20 mL). Yield: 57% (320 mg of a color-

1

less solid); mp 249 °C. H NMR (DMSO-d₆, 300 MHz): δ =

1.17 (t, 6 H), 1.94 (m_c, 1 H), 2.24 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s, 3

H), 2.84 (m_c, 1 H), 3.10 (m_c, 1 H), 3.70 (s, 3 H), 4.06 (m_c, 1 H),

5.28 (d, 1 H), 7.06 (s, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H), 8.00 (d,

1 H). HRMS calcd for C₂₃H₂₈N₃O₂m/z (MH^þ), 378.2175;

found, 378.2175. Anal. (C₂₃H₂₇N₃O₂): C, H, N.

(8S)-1-[(2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazol-5-yl)carbonyl]azetidine-2-carboxamide

(19). Preparation from carboxylic acid 7 (0.5 g, 1.5 mmol) and

azetidine-2-carboxamide (300 mg, 3.00 mmol) according to

general procedure 5/workup procedure 2. Eluant for column

chromatography: dichloromethane/methanol = 20:1 (v/v). Sol-

vent for washing: acetone (0.5 mL)/diethyl ether (20 mL)/

methanol (0.1 mL). Yield: 68% (430 mg of an orange solid);

(8S)-N-(Cyclopropylmethyl)-2,3-dimethyl-8-(2-methylphenyl)-

3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (26).

Preparation from carboxylic acid 7 (0.7 g, 2.1 mmol) and 1-cyclo-

propylmethanamine (200 μL, 162 mg, 2.3 mmol) according to

general procedure 5/workup procedure 1. Eluant for column chro-

matography: dichloromethane/methanol = 50:1 (v/v). Yield: 79%

(640 mg of an orange solid); mp 231 °C. ¹H NMR (DMSO-d₆, 400

MHz): δ=0.24(m_c, 2H), 0.44(m_c, 2H), 1.03(m_c, 1H), 1.93(m_c, 1

H), 2.23 (m_c, 1 H), 2.39 (s, 3 H), 2.48 (s, 3 H), 2.87 (m_c, 1 H), 3.12

(m_c, 3 H), 3.70 (s, 3 H), 5.29 (d, 1 H), 7.10 (s, 1 H), 7.27 (m_c, 3 H),

7.47 (m_c, 1 H), 8.27 (t, 1 H). HRMS calcd for C₂₄H₂₈N₃O₂m/z

(MH^þ), 390.2176; found, 390.2172.

1

mp 177-179 °C. H NMR (DMSO-d₆, 300 MHz, mixture of

stereoisomers): δ = 1.95 (m_c, 1 H), 2.19 (m_c, 1 H), 2.38 (s, 3 H),

2.47 (s, bs), 2.70-3.20 (m, 3 H), 3.70, 3.67-4.06 (s, m, 5 H), 4.71

(m_c, 1 H), 5.31 (m_c, 1 H), 7.01-7.53 (m, 7 H). HRMS calcd for

C₂₄H₂₇N₄O₃m/z (MH^þ), 419.2078; found, 419.2086.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-(2-oxopropyl)-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (27). Pre-

paration from carboxylic acid 7 (0.7 g, 2.1 mmol) and

1-aminoacetone hydrochloride (450 mg, 4.11 mmol) according

to general procedure 5/workup procedure 2. Eluant for column

chromatography: first column, dichloromethane/methanol =

13:1 (v/v); second column, ethyl acetate/triethylamine = 8:2 (v/

v). Solvent for washing: diethyl ether. Yield: 70% (570 mg of a

colorless solid, 99.2% ee). ¹H NMR (DMSO-d₆, 300 MHz): δ =

1.93 (m_c, 1 H), 2.16 (s, 3 H), 2.23 (m_c, 1 H), 2.39 (s, 3 H), 2.49 (s),

2.93 (m_c, 1 H), 3.14 (m_c, 1 H), 3.70 (s, 3 H), 4.06 (m_c, 2 H), 5.30

(d, 1 H), 7.18 (s, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H), 8.43 (t, 1 H).

HRMS calcd for C₂₃H₂₆N₃O₃m/z (MH^þ), 392.1969; found,

392.1974. Anal. (C₂₃H₂₅N₃O₃): H, N. For C: calcd, 70.57;

found, 69.94. HPLC analytical method: column, Chiralpak

AD-H 250 mm ꢀ 4.6 mm, 5 μm; eluant, ethanol/n-heptane =

20:80 (v/v); flow rate, 1 mL/min; temperature, 25 °C; t_R(8R) =

15.6 min/0.4 area %; t_R(8S) = 28.4 min/99.6 area %.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazole-5-carboxamide (20). Preparation from

carboxylic acid 7 (5.0 g, 15.0 mmol) and ammonia (6.5 mL of

a 7 M solution in methanol, 45.5 mmol) according to general

procedure 5. The reaction mixture was poured on saturated

sodium bicarbonate solution (400 mL). The phases were sepa-

rated and the aqueous phase extracted with dichloromethane

(3 ꢀ 300 mL). The combined organic phases were dried over

sodium sulfate and the solvent was evaporated. The title com-

pound was washed with a mixture of acetone (20 mL) and

diethyl ether (30 mL). Yield: 90% (4.5 g of a colorless solid). ¹H

NMR (DMSO-d₆, 300 MHz): δ = 1.94 (m_c, 1 H), 2.23 (m_c, 1 H),

2.38 (s, 3 H), 2.48 (s, 3 H), 2.95 (m_c, 1 H), 3.16 (m_c, 1 H), 3.69 (s, 3

H), 5.29 (d, 1 H), 7.18 (s, 1 H), 7.26 (m_c, 4 H), 7.47 (m_c, 1 H), 7.62

(bs, 1 H). HRMS calcd for C₂₀H₂₂N₃O₂m/z (MH^þ), 336.1707;

found, 336.1709.

(8S)-N-Ethyl-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide (22). Preparation

from carboxylic acid 7 (0.75 g, 2.2 mmol) and ethylamine

hydrochloride (360 mg, 4.4 mmol) according to general proce-

dure 5/workup procedure 2. Eluant for column chromatogra-

phy: dichloromethane/methanol = 50:1 (v/v). Solvent for

washing: diethyl ether (20 mL). Yield: 76% (610 mg of a color-

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-prop-2-yn-1-yl-3,6,

7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (28).

Preparation from carboxylic acid 7 (0.7 g, 2.1 mmol) and

prop-2-yn-1-amine (180 μL, 155 mg, 2.8 mmol) according to

general procedure 5/workup procedure 1. Eluant for column

chromatography: dichloromethane/methanol = 50:1 (v/v).

1

less solid); mp 258 °C. H NMR (DMSO-d₆, 300 MHz): δ =

Yield: 77% (600 mg of a yellow solid); mp 206 °C. H NMR

1.14 (t, 3 H), 1.92 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s,

3 H), 2.85 (m_c, 1 H), 3.11 (m_c, 1 H), 3.23 (q), 3.69 (s, 3 H), 5.29

(d, 1 H), 7.09 (s, 1 H), 7.26 (m_c, 3 H), 7.46 (m_c, 1 H), 7.99 (t, 1 H).

(DMSO-d₆, 400 MHz): δ = 1.93 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38

(s, 3 H), 2.49 (s), 2.86 (m_c, 1 H), 3.13 (m_c, 2 H), 3.70 (s, 3 H), 4.03

(m_c, 2 H), 5.30 (d, 1 H), 7.13 (s, 1 H), 7.27 (m_c, 3 H), 7.47 (m_c, 1 H),

3664 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

8.65 (t, 1 H). HRMS calcd for C₂₃H₂₄N₃O₂m/z (MH^þ),

374.1863; found, 374.1859.

(s, 3 H), 2.87 (m_c, 1 H), 3.12 (m_c, 1 H), 3.32 (m_c), 3.65, 3.69 (m_c, s,

4 H), 3.78 (m_c, 1 H), 3.99 (m_c, 1 H), 5.29 (d, 1 H), 7.10 (s, 1 H), 7.26

(m_c, 3 H), 7.47 (m_c, 1 H), 8.19 (m_c, 1 H). HRMS calcd for C₂₅H₃₀-

N₃O₃m/z (MH^þ), 420.2282; found, 420.2292.

(8S)-N-(Cyanomethyl)-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (29). Pre-

paration from carboxylic acid 7 (0.5 g, 1.5 mmol) and aminoa-

cetonitrile (168 mg, 3.0 mmol) according to general procedure

5/workup procedure 2. Eluant for column chromatography:

dichloromethane/methanol = 20:1 (v/v). Solvent for washing:

acetone (1 mL)/diethyl ether (10 mL). Yield: 75% (420 mg of a

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-(tetrahydro-2H-pyr-

an-2-ylmethyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-car-

boxamide (34). Preparation from carboxylic acid 7 (0.7 g, 2.1

mmol) and 1-tetrahydro-2H-pyran-2-ylmethanamine hydro-

chloride (630 mg, 4.2 mmol) according to general procedure 5/

workup procedure 1. Eluant for column chromatography:

dichloromethane/methanol. Yield: 91% (830 mg of a colorless

solid); mp 208 °C. ¹H NMR (DMSO-d₆, 400 MHz, mixture

of stereoisomers): δ = 1.20 (m_c, 1 H), 1.47 (bs, 3 H), 1.67 (m_c,

1 H), 1.80 (bs, 1 H), 1.93 (m_c, 1 H), 2.22 (m_c, 1 H), 2.38 (s,

3 H), 2.48 (s, 3 H), 2.85 (m_c, 1 H), 3.12 (m_c, 1 H), 3.24 (m_c, 2 H),

3.36, 3.43 (2 m_c, 2 H), 3.78 (s, 3 H), 3.89 (m_c, 1 H), 5.29 (dd, 1 H),

7.10 (m_c, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H), 8.13 (m_c, 1 H).

HRMS calcd for C₂₆H₃₂N₃O₃m/z (MH^þ), 434.2438; found,

434.2437.

(8S)-N-(2-Methoxyethyl)-2,3-dimethyl-8-(2-methylphenyl)-3,6,

7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (35). Pre-

paration from carboxylic acid 7 (0.50 g, 1.5 mmol) and

2-methoxyethylamine (170 μL, 1.9 mmol) according to general

procedure 7/workup procedure 1. Eluant for column chroma-

tography: ethyl acetate/ethanol = 10:1 (v/v). Yield: 36% (310 mg

of a colorless solid). ¹H NMR (DMSO-d₆, 400 MHz): δ = 1.92

(m_c, 1 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H), 2.48 (s, 3 H), 2.86 (m_c, 1 H),

3.12 (m_c, 1 H), 3.31 (s), 3.41 (m_c, 2 H), 3.48 (m_c, 2 H), 3.69 (s, 3 H),

5.29 (d, 1 H), 7.10 (s, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H), 8.19 (t, 1

H). HRMS calcd for C₂₃H₂₈N₃O₃m/z (MH^þ), 394.2125; found,

394.2127. Anal. (C₂₃H₂₇N₃O₃): C, H, N.

(8S)-N-(2-Methoxyethyl)-N,2,3-trimethyl-8-(2-methylphenyl)-

3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (36).

Preparation from carboxylic acid 7 (0.70 g, 2.1 mmol) and

N-(methoxyethyl)methylamine (230 mg, 2.6 mmol) according

to general procedure 7/workup procedure 1. Eluant for column

chromatography: first column, ethyl acetate/ethanol = 50:1 (v/

v); second column, ethyl acetate/ethanol = 150:1 (v/v). Yield:

21% (batch 1 obtained after first column, 180 mg of a colorless

foam)/20% (batch 2 obtained after second column, 170 mg of a

slightly yellow oil). ¹H NMR (DMSO-d₆, 300 MHz, 110 °C): δ =

2.04 (m_c, 1 H), 2.23 (m_c, 1 H), 2.39 (s, 3 H), 2.46 (s, 3 H), 2.69 (m_c,

1 H), 2.87, 2.88 (s, m_c, 7 H), 3.51 (bs, 4 H), 3.66 (s, 3 H), 5.32 (d, 1

H), 6.83 (s, 1 H), 7.21 (m_c, 3 H), 7.45 (m_c, 1 H). HRMS calcd for

C₂₄H₃₀N₃O₃m/z (MH^þ), 408.2282; found, 408.2284.

1

pale-yellow solid); mp 241-242 °C. H NMR (DMSO-d₆, 400

MHz): δ = 1.93 (m_c, 1 H), 2.24 (m_c, 1 H), 2.39 (s, 3 H), 2.49 (s),

2.87 (m_c, 1 H), 3.15 (m_c, 1 H), 3.71 (s, 3 H), 4.30 (d, 2 H), 5.31 (d,

1 H), 7.20 (s, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H), 8.90 (t, 1 H).

HRMS calcd for C₂₂H₂₃N₄O₂m/z (MH^þ), 375.1816; found,

375.1822.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-[2-(methylsulfanyl)-

ethyl]-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxa-

mide (30). Preparation from carboxylic acid 7 (0.8 g, 2.4 mmol)

and 2-(methylthio)ethanamine (430 μL, 421 mg, 4.6 mmol)

according to general procedure 7/workup procedure 1. Eluant

for column chromatography: dichloromethane/methanol =

50:1 (v/v). Yield: 54% (530 mg of an off-white solid); mp

1

210 °C. H NMR (DMSO-d₆, 300 MHz): δ = 1.93 (m_c, 1 H),

2.12 (s, 3 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H), 2.48 (s), 2.67 (t, 2 H),

2.89 (m_c, 1 H), 3.13 (m_c, 1 H), 3.42 (m_c, 2 H), 3.69 (s, 3 H), 5.29

(dd, 1 H), 7.11 (s, 1 H), 7.26 (m_c, 3 H), 7.46 (m_c, 1 H), 8.27 (t,

1 H). HRMS calcd for C₂₃H₂₈N₃O₂S m/z (MH^þ), 410.1897;

found, 410.1898.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-[2-(methylsulfinyl)-

ethyl]-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxa-

mide (31). An aqueous solution of sodium periodate (175 mg,

0.82 mmol, in 1 mL of water) was added to a solution of sulfide

30 (200 mg, 0.60 mmol) in methanol (8 mL). The colorless

suspension was stirred for 1 h at room temperature and poured

on a mixture of water (12 mL) and dichloromethane (20 mL).

The phases were separated, and the aqueous phase was extracted

with dichloromethane (2 ꢀ 5 mL). The combined organic phases

were washed with water (1ꢀ), dried over sodium sulfate, and the

solvent was evaporated. The residue (230 mg of a colorless solid)

was purified by column chromatography [60 g of silica gel,

eluant: dichloromethane/methanol = 20:1 (v/v)] and washed

with diethyl ether. The title compound was isolated in 43% yield

(90 mg of a colorless solid); mp 150-152 °C. ¹H NMR (DMSO-

d₆, 300 MHz): δ = 1.94 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H),

2.48 (s, 3 H), 2.62 (s, 3 H), 2.91 (m_c, 2 H), 3.11 (m_c, 2 H), 3.61 (m_c,

2 H), 3.69 (s, 3 H), 5.30 (d, 1 H), 7.14 (d, 1 H), 7.26 (m_c, 3 H), 7.46

(m_c, 1 H), 8.42 (t, 1 H).

(8S)-N-Methoxy-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-tetra-

hydrochromeno[7,8-d]imidazole-5-carboxamide (37). Prepara-

tion from carboxylic acid 7 (0.75 g, 2.2 mmol) and O-methylhy-

droxylamine hydrochloride (360 mg, 4.3 mmol) according to

general procedure 5/workup procedure 1. Eluant for column

chromatography: dichloromethane/methanol = 50:1 (v/v).

Subsequent crystallization of the title compound (430 mg of a

yellow foam) from 2-propanol. Yield: 30% (240 mg of a color-

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-oxetan-3-yl-3,6,7,8-

tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (32). Pre-

paration from carboxylic acid 7 (0.50 g, 1.5 mmol) and oxe-

tan-3-amine hydrochloride (412 mg, 3.76 mmol) according to

general procedure 5/workup procedure 2. Eluant for column

chromatography: dichloromethane/methanol = 20:1 (v/v). Sol-

vent for washing: acetone (0.5 mL)/diethyl ether (10 mL). Yield:

1

less solid); mp 160 °C. H NMR (DMSO-d₆, 300 MHz): δ =

1

65% (381 mg of a colorless solid); mp 274-275 °C. H NMR

1.98 (m_c, 1 H), 2.26 (m_c, 1 H), 2.39 (s, 3 H), 2.53 (s, 3 H), 2.88 (m_c,

1 H), 3.13 (m_c, 1 H), 3.74 (s, 6 H), 5.34 (d, 1 H), 7.21 (s, 1 H), 7.27

(m_c, 3 H), 7.46 (m_c, 1 H), 11.41 (bs, 1 H). HRMS calcd for

C₂₁H₂₄N₃O₃m/z (MH^þ), 366.1812; found, 366.1811.

(DMSO-d₆, 300 MHz): δ = 1.94 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38

(s, 3 H), 2.48 (s, 3 H), 2.85 (m_c, 1 H), 3.12 (m_c, 1 H), 3.71 (s, 3 H),

4.59 (m_c, 2 H), 4.79 (m_c, 2 H), 4.98 (m_c, 1 H), 5.29 (d, 1 H), 7.19

(s, 1 H), 7.26 (m_c, 3 H), 7.46 (m_c, 1 H), 8.90 (d, 1 H). HRMS calcd

for C₂₃H₂₆N₃O₃m/z (MH^þ), 392.1969; found, 392.1969. Anal.

(C₂₃H₂₅N₃O₃): C, H, N.

(8S)-N-Methoxy-N,2,3-trimethyl-8-(2-methylphenyl)-3,6,7,8-

tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (38). Pre-

paration from carboxylic acid 7 (0.8 g, 2.4 mmol) and N,O-

dimethylhydroxylamine hydrochloride (700 mg, 7.2 mmol) ac-

cording to general procedure 7/workup procedure 1. Eluant for

column chromatography: dichloromethane/methanol = 50:1 (v/

v). Yield: 64% (580 mg of a brown solid); mp 168 °C. ¹H NMR

(DMSO-d₆, 300 MHz): δ=1.98(m_c, 1H), 2.23(m_c, 1H), 2.38(s, 3

H), 2.47 (s, 3 H), 2.68 (m_c, 1 H), 2.97 (m_c, 1 H), 3.22 (s, 3 H), 3.55 (s,

3 H), 3.69 (s, 3 H), 5.31 (dd, 1 H), 7.04 (s, 1 H), 7.25 (m_c, 3 H), 7.47

(m_c, 1 H). HRMS calcd for C₂₂H₂₆N₃O₃m/z (MH^þ), 380.1969;

found, 380.1968. Anal. (C₂₂H₂₅N₃O₃): C, H, N.

(8S)-2,3-Dimethyl-8-(2-methylphenyl)-N-(tetrahydrofuran-2-

ylmethyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxa-

mide (33). Preparation from carboxylic acid 7 (0.7 g, 2.1 mmol)

and 1-tetrahydrofuran-2-ylmethanamine (430 μL, 421 mg, 4.2 mmol)

according to general procedure 5/workup procedure 1. Eluant

for column chromatography: dichloromethane/methanol = 10:1

(v/v). Yield: 74% (650 mg of a yellow solid); mp 201 °C. ¹H NMR

(DMSO-d₆, 400 MHz, mixture of stereoisomers): δ = 1.63 (m_c,

1 H), 1.84 (m_c, 2 H), 1.94 (m_c, 2 H), 2.22 (m_c, 1 H), 2.38 (s, 3 H), 2.48

Article

[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochro-

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3665

(8S)-8-(4-Chloro-2-methylphenyl)-N,2,3-trimethyl-3,6,7,8-

tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (129). Pre-

paration from carboxylic acid 126 (600 mg, 1.6 mmol) and

methylamine (2 N solution in THF, 1.60 mL, 3.2 mmol) accor-

ding to general procedure 5/workup procedure 2. Eluant for

column chromatography: dichloromethane/methanol = 20:1

(v/v). Slurrying in acetone (0.5 mL) and diethyl ether (10 mL).

meno[7,8-d]imidazol-5-yl](morpholin-4-yl)methanone (40). Pre-

paration from carboxylic acid 7 (0.8 g, 2.4 mmol) and morpho-

line (420 μL, 4.8 mmol) according to general procedure

7/workup procedure 1. Eluant for column chromatography:

dichloromethane/methanol. Yield: 76% (740 mg of a colorless

1

solid); mp 212 °C. H NMR (DMSO-d₆, 300 MHz): δ = 1.97

1

Yield: 53% (324 mg of a colorless solid); mp 130-132 °C. H

(bs, 1 H), 2.22 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.59-3.10

(bm, 2 H), 3.22 (bs, 2 H), 3.44, 3.54, 3.68 (3 bs, 9 H), 5.33 (d, 1 H),

6.96 (s, 1 H), 7.26 (m_c, 3 H), 7.46 (m_c, 1 H). HRMS calcd for

C₂₄H₂₈N₃O₃m/z (MH^þ), 406.2125; found, 406.2112. Anal.

(C₂₄H₂₇N₃O₃): C, H, N.

NMR (DMSO-d₆, 300 MHz): δ = 1.89 (m_c, 1 H), 2.21 (m_c, 1 H),

2.38 (s, 3 H), 2.48 (s, 3 H), 2.76 (d, 3 H), 2.85 (m_c, 1 H), 3.12 (m_c, 1

H), 3.69 (s, 3 H), 5.28 (d, 1 H), 7.13 (s, 1 H), 7.33 (m_c, 2 H), 7.47

(m_c, 1 H), 8.08 (q, 1 H). HRMS calcd for C₂₁H₂₃ClN₃O₂m/z

(MH^þ), 384.1473; found, 384.1483.

(8S)-N⁰-Acetyl-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-tetra-

hydrochromeno[7,8-d]imidazole-5-carbohydrazide (41). Prepara-

tion from carboxylic acid 7 (0.70 g, 2.1 mmol) and acetohydra-

zide (593 mg, 8.0 mmol) according to general procedure

5/workup procedure 2. Purification: washing with methanol (1

mL) and diethyl ether (10 mL) instead of column chromatog-

raphy. Yield: 75% (616 mg of a light-yellow solid); mp 240-

242 °C. ¹H NMR (DMSO-d₆, 400 MHz): δ = 1.93, 1.96 (s, m_c,

4 H), 2.25 (m_c, 1 H), 2.39 (s, 3 H), 2.50 (s), 2.96 (m_c, 1 H), 3.14

(m_c, 1 H), 3.74 (s, 3 H), 5.34 (dd, 1 H), 7.25 (m_c, 4 H), 7.48 (m_c, 1

H), 9.89 (bs, 1 H), 9.98 (bs, 1 H).

(8S)-2,3-Dimethyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-8-(2-methyl-

phenyl)-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole (42). A

solution of carbohydrazide 41 (580 mg, 1.48 mmol) in phosphorus

oxychloride (4.8 mL) was heated at 50 °C for 1 h. The reaction

mixture was poured on a mixture of ice-water (50 mL) and

dichloromethane (50 mL) and a pH value of 8 was adjusted by

addition of 6 N sodium hydroxide solution. The phases were

separated, and the aqueous phase was extracted with dichloro-

methane (2 ꢀ 20 mL). The combined organic phases were dried

over sodium sulfate, and the solvent was evaporated. The residue

(530 mg of a yellow oil) was purified by column chromatography

[50 g of silica gel, eluant: dichloromethane/methanol = 50:1 (v/v)].

Evaporation of the corresponding fractions afforded a solid

residue (240 mg), which was washed with diethyl ether (10 mL).

The title compound was isolated in 42% yield (230 mg of a

colorless solid); mp 190-192 °C. ¹H NMR (DMSO-d₆, 300 MHz):

δ = 2.01 (m_c, 1 H), 2.32 (m_c, 1 H), 2.40 (s, 3 H), 2.52 (s, 3 H), 2.60

(s, 3 H), 3.25 (m_c, 2 H), 3.76 (s, 3 H), 5.37 (dd, 1 H), 7.27 (m_c, 3 H),

7.49 (m_c, 1 H), 7.62 (s, 1 H). HRMS calcd for C₂₂H₂₃N₄O₂m/z

(MH^þ), 375.1816; found, 375.1816. Anal. (C₂₂H₂₂N₄O₂): H, N.

For C: calcd, 70.57; found, 69.82.

Azetidin-1-yl[(8S)-8-(4-chloro-2-methylphenyl)-2,3-dimethyl-3,

6,7,8-tetrahydrochromeno[7,8-d]imidazol-5-yl]methanone (130).

Preparation from carboxylic acid 126 (600 mg, 1.6 mmol) and

azetidine (215 μL, 3.2 mmol) according to general procedure 5/

workup procedure 2. Eluant for column chromatography:

dichloromethane/methanol = 20:1 (v/v). Slurrying in acetone

(0.5 mL) and diethyl ether (10 mL). Yield: 53% (350 mg of a

slightly yellow solid). ¹H NMR (DMSO-d₆, 300 MHz): δ = 1.92

(m_c, 1 H), 2.22 (m_c, 3 H), 2.39 (s, 3 H), 2.47 (s, 3 H), 2.80 (m_c, 1

H), 3.04 (m_c, 1 H), 3.69 (s, 3 H), 3.87 (m_c, 1 H), 4.01 (m_c, 3 H),

5.30 (d, 1 H), 7.04 (s, 1 H), 7.33 (m_c, 2 H), 7.47 (m_c, 1 H). HRMS

calcd for C₂₃H₂₅ClN₃O₂m/z (MH^þ), 410.1630; found,

410.1636.

(8S)-8-(4-Chloro-2-methylphenyl)-5-[(3-methoxyazetidin-1-yl)-

carbonyl]-2,3-dimethyl-3,6,7,8-tetrahydrochromeno[7,8-d]imida-

zole (131). Preparation from carboxylic acid 126 (500 mg, 1.35

mmol) and 3-methoxyazetidine hydrochloride (334 mg, 2.70

mmol) according to general procedure 5/workup procedure 2.

Eluant for column chromatography: dichloromethane/metha-

nol = 50:1 (v/v). Solvent for crystallization: acetone (0.5 mL)/

petroleum ether (5 mL). Yield: 47% (280 mg of a pale-yellow

solid); mp 193-195 °C. ¹H NMR (DMSO-d₆, 300 MHz): δ =

1.92 (m_c, 1 H), 2.22 (m_c, 1 H), 2.39 (s, 3 H), 2.47 (s, 3 H), 2.78 (m_c,

1 H), 3.01 (m_c, 1 H), 3.21 (d, 3 H), 3.70 (s, 3 H), 3.87, 4.01, 4.20 (3

m_c, 5 H), 5.31 (d, 1 H), 7.07 (s, 1 H), 7.33, 7.34 (s, d, 2 H), 7.47 (d,

1 H). HRMS calcd for C₂₄H₂₇ClN₃O₃m/z (MH^þ), 440.1735;

found, 440.1740. Anal. (C₂₄H₂₆ClN₃O₃): H, N. For C: calcd,

65.52; found, 65.04.

5.1.4. Synthesis and Asymmetric Reduction of Ketones. Mit-

sunobu Cyclization to 3,6,7,8-Tetrahydrochromeno[7,8-d]imida-

zoles. General Procedure 8 (Transformation of Mannich Bases

into Ketones). A suspension of the Mannich base in toluene

(0.1-0.5 M) was heated to 100 °C and the respective 1-[1-(aryl)-

vinyl]-pyrrolidine (1.4 -2.5 equiv) was added dropwise. The

reaction mixture was kept at 100 °C for 2.5-4 h. After cooling to

room temperature, the solvent was evaporated in vacuo and the

residue was purified as described below. The required

1-[1-(aryl)-vinyl]-pyrrolidines were prepared by titanium tetra-

chloride mediated condensation of the respective acetophenone

derivative with pyrrolidine, see lit.³⁷

(8S)-8-(4-Chlorophenyl)-N,2,3-trimethyl-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazole-5-carboxamide (127). Preparation

from carboxylic acid 125 (750 mg, 2.1 mmol) and methylamine

(2 N solution in THF, 2.10 mL, 4.2 mmol) according to general

procedure 7. The reaction mixture was concentrated to a volume

of 10 mL, and diethyl ether (10 mL) added. After a period of 30

min, the title compound was isolated by filtration: 570 mg of a

1

colorless solid (73% yield); mp 317 °C. H NMR (DMSO-d₆,

300 MHz): δ = 1.97 (m_c, 1 H), 2.23 (m_c, 1 H), 2.49 (s), 2.75, 2.78

(d, m_c, 4 H), 3.03 (m_c, 1 H), 3.69 (s, 3 H), 5.22 (dd, 1 H), 7.12 (s, 1

H), 7.49 (m_c, 4 H), 8.08 (q, 1 H). HRMS calcd for C₂₀H₂₁ClN₃O₂

m/z (MH^þ), 370.1317; found, 370.1310. Anal. (C₂₀H₂₀ClN₃O₂):

C, H, N.

Azetidin-1-yl[(8S)-8-(4-chlorophenyl)-2,3-dimethyl-3,6,7,8-

tetrahydrochromeno[7,8-d]imidazol-5-yl]methanone (128). Pre-

paration from carboxylic acid 125 (750 mg, 2.1 mmol) and

azetidine (350 μL, 5.2 mmol) according to general procedure

5/workup procedure 2. Eluant for column chromatography:

dichloromethane/methanol = 30:1 (v/v). Slurrying in diethyl

ether. Yield: 72% (600 mg of a colorless solid); mp 281 °C. ¹H

NMR (DMSO-d₆, 300 MHz): δ = 2.01 (m_c, 1 H), 2.22 (m_c, 3 H),

2.48 (s, 3 H), 2.73 (m_c, 1 H), 2.95 (m_c, 1 H), 3.69 (s, 3 H), 3.85 (m_c,

1 H), 4.02 (m_c, 3 H), 5.24 (dd, 1 H), 7.04 (s, 1 H), 7.49 (m_c, 4 H).

HRMS calcd for C₂₂H₂₃ClN₃O₂m/z (MH^þ), 396.1473; found,

396.1471.

5-[3-(2-Cyclopropylphenyl)-3-oxopropyl]-4-hydroxy-N,N,1,2-

tetramethyl-1H-benzimidazole-6-carboxamide (51). The title

compound was prepared from Mannich base 46 (12.0 g, 41.3

mmol) and 1-[1-(2-cyclopropylphenyl)vinyl]pyrrolidine (12.1 g,

56.4 mmol) as described in general procedure 8. The crude

product was purified by column chromatography [silica gel,

eluant: dichloromethane, then dichloromethane/methanol =

20:1 (v/v)] and crystallization from 2-propanol: 8.7 g of an off-

white solid (52% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ =

0.64 (m_c, 2 H), 0.91 (m_c, 2 H), 2.22 (m_c, 1 H), 2.50 (s, 3 H), 2.61

(bm_c, 1 H), 2.76 (s, 3 H), 2.98, 3.07 (s, bs, 6 H), 3.66 (s, 3 H), 6.77

(s, 1 H), 7.04 (m_c, 1 H), 7.24 (m_c, 1 H), 7.38 (m_c, 1 H), 7.48 (m_c, 1

H), 9.97 (bs, 1 H). HRMS calcd for C₂₄H₂₈N₃O₃m/z (MH^þ),

406.2125; found, 406.2123.

5-[3-(4-Chlorophenyl)-3-oxopropyl]-4-hydroxy-N,N,1,2-tetra-

methyl-1H-benzimidazole-6-carboxamide (54). The title com-

pound was prepared from Mannich base 46 (31.5 g, 108.5

3666 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

mmol) and 1-[1-(4-chlorophenyl)vinyl]pyrrolidine (56.0 g, 270.5

mmol) as described in general procedure 8. The crude product

was purified by column chromatography [450 g of silica gel,

eluant: dichloromethane, then dichloromethane/metha-

nol = 20:1 (v/v)] and crystallization from acetone (50 mL):

14.0 g of a colorless solid (32% yield); mp 258-260 °C. ¹H NMR

(DMSO-d₆, 400 MHz): δ = 2.53 (s, 3 H), 2.78, 3.00, 3.15 (2 s, bs,

10 H), 3.69 (s, 3 H), 6.79 (s, 1 H), 7.58 (d, 2 H), 7.98 (d, 2 H), 9.95

(bs, 1 H). HRMS calcd for C₂₁H₂₃ClN₃O₃m/z (MH^þ),

400.1422; found, 400.1419. Anal. (C₂₁H₂₂ClN₃O₃): C, H, N.

5-[3-(4-Chloro-2-methylphenyl)-3-oxopropyl]-4-hydroxy-N,N,

1,2-tetramethyl-1H-benzimidazole-6-carboxamide (56). The title

compound was prepared from Mannich base 46 (9.4 g, 32.4

mmol) and 1-[1-(4-chloro-2-methylphenyl)vinyl]pyrrolidine

(11.5 g, 51.8 mmol) as described in general procedure 8. A

suspension of the crude product in diisopropyl ether (100 mL)

was stirred for 16 h at room temperature, and the precipitate was

isolated by filtration. At a temperature of 50 °C, fumaric acid

(1.9 g) was added to a solution of the obtained solid in

2-propanol (100 mL). After a period of 1 h at room temperature,

the precipitate was isolated by filtration. The solid was dissolved

in dichloromethane and saturated sodium bicarbonate solution.

The phases were separated and the aqueous phase was extracted

with dichloromethane (3 ꢀ 50 mL). The combined organic

phases were dried over magnesium sulfate, and the solvent

was evaporated. The residue was crystallized from a mixture

of diisopropyl ether (80 mL) and ethyl acetate (20 mL). The title

compound was isolated by filtration and dried in vacuo (7.1 g,

53% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ = 2.41 (s, 3 H),

2.52 (s), 2.77 (s, 4 H), 2.99, 3.06 (s, bs, 5 H), 3.30 (bs), 3.69 (s, 3

H), 6.78 (s, 1 H), 7.37 (m_c, 2 H), 7.74 (d, 1 H), 10.13 (bs, 1 H).

HRMS calcd for C₂₂H₂₅ClN₃O₃m/z (MH^þ), 414.1579; found,

414.1577. Anal. (C₂₂H₂₄ClN₃O₃): C, H, N.

5-[3-(2-Chloro-4-fluorophenyl)-3-oxopropyl]-4-hydroxy-N,N,1,

2-tetramethyl-1H-benzimidazole-6-carboxamide (57). The title

compound was prepared from Mannich base 46 (41.5 g, 143

mmol) and 1-[1-(2-chloro-4-fluorophenyl)vinyl]pyrrolidine

(65.2 g, 289 mmol) as described in general procedure 8

(reaction temperature: 70 °C). The crude product was purified

by column chromatography [silica gel, eluant: dichloromethane/

methanol = 95:5 (v/v)]. The resulting yellow oil was dissolved in

acetone (200 mL), and fumaric acid (16.6 g, 143 mmol) was

added. The suspension was stirred for 3 d at room temperature

and the precipitate was isolated by filtration. The salt of the title

compound with fumaric acid was washed with acetone, dried in

vacuo at a temperature of 40 °C, dissolved in dichloromethane,

and treated with saturated sodium bicarbonate solution (250

mL). The phases were separated, and the aqueous phase was

extracted with dichloromethane (3ꢀ). The combined organic

phases were washed with water (80 mL), dried over sodium

sulfate, and the solvent was evaporated. This afforded a 80:20

mixture of the title compound with 5-[3-(2-chloro-4-pyrrolidin-

1-ylphenyl)-3-oxopropyl]-4-hydroxy-N,N,1,2-tetramethyl-1H-

benzimidazole-6-carboxamide (46.1 g, 77% yield). The com-

pounds were separated by column chromatography [silica gel,

eluant: ethyl acetate/methanol = 95:5 to 9:1 (v/v)] and obtained

in 45% yield (26.7 g of title compound) and 9% yield (6.1 g of

byproduct), respectively. ¹H NMR (CDCl₃, 400 MHz): δ = 2.61

(s, 3 H), 2.77, 2.87 (bs, s, 4 H), 3.15 (s, 3 H), 3.35 (m_c, 3 H), 3.66

(s, 3 H), 6.69 (s, 1 H), 6.99 (m_c, 1 H), 7.13 (m_c, 1 H), 7.65 (m_c,

1 H), 11.80 (bs, 1 H). HRMS calcd for C₂₁H₂₂ClFN₃O₃m/z

(MH^þ), 418.1328; found, 418.1316. Anal. (C₂₁H₂₁ClFN₃O₃): C,

H, N.

precipitate was isolated by filtration. The crude title compound

was suspended in acetone (100 mL), and fumaric acid (5.45 g)

was added at reflux temperature. The mixture was stirred for 1 h

at reflux and cooled to room temperature. The salt of the title

compound with fumaric acid was isolated by filtration and

suspended in dichloromethane (150 mL). The title compound

was released by treatment with 1 N sodium hydroxide solution

(3 ꢀ 50 mL). The organic phase was dried over magnesium

sulfate, and the solvent was evaporated. The residue was slurried

in 2-propanol (40 mL): 7.3 g of an off-white solid (36% yield).

¹H NMR (DMSO, 200 MHz): δ = 2.52 (s), 2.77, 2.80 (s, bs, 4

H), 2.98, 3.05 (s, m_c, 6 H), 3.66 (s, 3 H), 6.78 (s, 1 H), 7.54 (m_c, 1

H), 7.65 (m_c, 1 H), 7.73 (m_c, 1 H), 10.03 (bs, 1 H). HRMS calcd

for C₂₁H₂₂Cl₂N₃O₃m/z (MH^þ), 434.1033; found, 434.1036.

4-Hydroxy-N,N,1,2-tetramethyl-5-[3-(naphthalen-2-yl)-3-oxo-

propyl]-1H-benzimidazole-6-carboxamide (59). The title com-

pound was prepared from Mannich base 46 (2.6 g, 9.0 mmol)

and 1-(1-naphthalen-2-yl-vinyl)pyrrolidine (3.45 g, 15.4 mmol)

as described in general procedure 8. The crude product was

dissolved in acetone (100 mL), fumaric acid (1.2 g) was added,

and the solution was stirred overnight at room temperature. The

precipitate was isolated by filtration and washed with acetone

(2 ꢀ 20 mL). The salt of the title compound with fumaric acid

was dissolved in dichloromethane (100 mL), and aqueous

ammonia was added until a pH value of 9 was reached. The

phases were separated, and the aqueous phase was extracted

with dichloromethane (3 ꢀ 50 mL). The combined organic

phases were dried over magnesium sulfate and concentrated in

vacuo. The title compound was purified by column chromatog-

raphy [silica gel, eluant: dichloromethane/methanol = 15:1 (v/

v)] and crystallization from acetone: 0.48 g of a colorless solid

1

(13% yield); mp 221-225 °C. H NMR (DMSO, 200 MHz):

δ = 2.54 (s, bs), 2.79, 2.90, 3.00 (s, bs, s, 9 H), 3.69 (s, 3 H), 6.81

(s, 1 H), 7.64 (m_c, 2 H), 8.00 (m_c, 3 H), 8.16 (m_c, 1 H), 8.72 (m_c,

1 H), 10.04 (bs, 1 H). HRMS calcd for C₂₅H₂₆N₃O₃m/z (MH^þ),

416.1969; found, 416.1964.

General Procedure 9 (Asymmetric Hydrogenation of Ketones).

In a flask filled with argon, the corresponding ketone was

suspended in 2-propanol and potassium tert-butylate solution

(1 M in tert-butanol, 1.1 equiv) was slowly added (final substrate

concentration 0.20-0.46 M). At a temperature of 50 °C, the

hydrogenation catalyst RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN]

82 (S/C = 100:1) was added and stirring was continued for

several minutes. The suspension was transferred into an auto-

clave, purged with hydrogen (3ꢀ), and hydrogenated at 70 °C

and 80 bar pressure for 16-20 h. After cooling to room

temperature and releasing of the hydrogen pressure, the reaction

mixture was poured on saturated ammonium chloride solution.

The mixture was extracted with dichloromethane (4ꢀ). The

combined organic phases were dried over magnesium sulfate

or sodium sulfate, and the solvent was evaporated. The residue

was slurried in acetone. The title compound was isolated by

filtration and dried in vacuo.

The optical purity of the title compound was determined

either by HPLC (column: Daicel Chiralpak AD-H, 250 mm ꢀ

4.6 mm, 5 μm, flow rate: 1 mL/min, detection wavelength:

218 nm) or by capillary electrophoresis (instrument: Agilent

CE-3D; capillary: Agilent 56/64.5 cm ꢀ 50 μm bare fused silica

bubble; buffer: 50 mM sodium phosphate, pH 2.5; chiral

selector: 40 mM heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin;

voltage: 30 kV; temperature: 20 °C; detection wavelength:

219/226 nm).

5-[(3R)-3-(2-Cyclopropylphenyl)-3-hydroxypropyl]-4-hydro-

xy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (93).

The title compound was prepared by asymmetric reduction of

ketone 51 (6.7 g, 16.5 mmol) as described in general procedure 9.

Purification by column chromatography [silica gel, eluant:

dichloromethane/methanol = 10:1 (v/v)] instead of slurrying

in acetone: 4 g of a slightly green foam (61% yield, 92.6% ee).

HPLC analytical method: t_R(3R) = 8.5 min/96.3 area %; t_R

5-[3-(2,4-Dichlorophenyl)-3-oxopropyl]-4-hydroxy-N,N,1,2-

tetramethyl-1H-benzimidazole-6-carboxamide (58). The title

compound was prepared from Mannich base 46 (13.7 g, 47.0

mmol) and 1-[1-(2,4-dichlorophenyl)vinyl]pyrrolidine (18.2 g,

75.3 mmol) as described in general procedure 8. A suspension of

the crude product in diisopropyl ether (200 mL) was stirred for

30 min at reflux and for 17 h at room temperature. The

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3667

(3S) = 11.2 min/3.7 area %. ¹H NMR (DMSO-d₆, 400 MHz):

δ = 0.57 (m_c, 2 H), 0.83 (m_c, 2 H), 1.60-2.05, 1.92 (bs, m_c, 2 H),

2.50 (s), 2.59 (bs, 1 H), 2.70 (s, 3 H), 2.92 (s, 4 H), 3.65 (s, 3 H),

5.05 (bs, 2 H), 6.71 (s, 1 H), 6.89 (m_c, 1 H), 7.11 (m_c, 2 H), 7.43

(m_c, 1 H), 9.77 (bs, 1 H). HRMS calcd for C₂₄H₃₀N₃O₃m/z

(MH^þ), 408.2282; found, 408.2276.

4-Hydroxy-5-[(3R)-3-hydroxy-3-(naphthalen-2-yl)propyl]-N,

N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (101). The

catalyst RuCl₂[(S)-Xyl-PPhos][(S)-DAIPEN] 82 (12 mg) and

ketone 59 (400 mg, 1.0 mmol) were weighed in the glass liner

and placed in a Parr microreactor (volume: 25 mL) that was

purged with nitrogen (5ꢀ) and hydrogen (5ꢀ). Potassium tert-

butylate solution (1 M in tert-butanol, 2.75 mL) and 2-propanol

(2.5 mL) was added. The autoclave was then purged with

hydrogen without stirring (5ꢀ) and with stirring (5ꢀ). The

reaction mixture was stirred at a hydrogen pressure of 25-30

bar and a temperature of 65 °C for 20 h. After cooling to room

temperature, the solvent was evaporated. The residue was

dissolved in dichloromethane and washed with saturated am-

monium chloride solution. The aqueous phase was extracted

several times with dichloromethane. The combined organic

layers were dried over sodium sulfate and concentrated in vacuo,

leading to a green solid (340 mg). The conversion (100%) was

measured by HPLC. A part of the crude product (300 mg) was

purified by column chromatography on silica gel [eluant: di-

chloromethane/methanol = 15:1 (v/v)]. This afforded the pure

title compound (164 mg of a green solid, 39% yield, 45%

corrected yield, ee determined after Mitsunobu cyclization to

5-[(3R)-3-(4-Chlorophenyl)-3-hydroxypropyl]-4-hydroxy-N,

N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (96). The

title compound was prepared by asymmetric reduction of

ketone 54 (10.0 g, 25.0 mmol) as described in general procedure

9. The diol 96 precipitated when the reaction mixture was

poured on a stirred mixture of saturated ammonium chloride

solution (100 mL), dichloromethane (100 mL), and methanol

(30 mL). The title compound was isolated by filtration and dried

in vacuo: 6.0 g (60% yield, 68.0% ee). The organic phase of the

filtrate was concentrated, and the sparingly soluble residue was

washed with acetone (20 mL). This afforded a second batch of

the title compound (30% yield, 70.8% ee). CE analytical

method: t_M(3S) = 26.4 min/16.0 (14.6) area %; t_M(3R) =

26.9 min/84.0 (85.4) area %; mp 290-291 °C. ¹H NMR

(DMSO-d₆, 300 MHz): δ = 1.55-2.00 (m, 2 H), 2.15-2.50

(m), 2.50 (s), 2.67 (s, m_c, 4 H), 2.88 (s, 3 H), 3.64 (s, 3 H), 4.49 (t, 1

H), 5.24 (bs, 1 H), 6.69 (s, 1 H), 7.34 (m_c, 4 H), 9.75 (bs, 1 H).

HRMS calcd for C₂₁H₂₅ClN₃O₃m/z (MH^þ), 402.1579; found,

402.1580.

5-[(3R)-3-(4-Chloro-2-methylphenyl)-3-hydroxypropyl]-4-hy-

droxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (98).

The title compound was prepared by asymmetric reduction of

ketone 56 (7.0 g, 16.9 mmol) as described in general procedure 9:

5.6 g of a colorless solid (84% yield, 90.6% ee). HPLC analytical

method: eluant, n-heptane/ethanol = 80:20 (v/v); t_R(3R) =

19.4 min/95.3 area %; t_R(3S) = 25.4 min/4.7 area %. ¹H NMR

(DMSO-d₆, 300 MHz): δ = 1.50-2.00 (m, 2 H), 2.21 (s, bs, 4 H),

2.50 (s, m_c), 2.69 (s, 3 H), 2.92 (s, 3 H), 3.64 (s, 3 H), 4.67 (bs, 1

H), 5.14 (bs, 1 H), 6.71 (s, 1 H), 7.20 (m_c, 2 H), 7.41 (d, 1 H), 9.80

(bs, 1 H). HRMS calcd for C₂₂H₂₇ClN₃O₃m/z (MH^þ),

416.1735; found, 416.1729. Anal. (C₂₂H₂₆ClN₃O₃): C, H. For

N: calcd, 10.10; found, 9.54.

1

118); mp 145-147 °C. H NMR (DMSO-d₆, 400 MHz): δ =

1.81 (bs, 1 H), 2.01 (bs, 1 H), 2.50 (s, bs), 2.66 (s, 3 H), 2.78 (s, bs,

4 H), 3.64 (s, 3 H), 4.66 (bs, 1 H), 5.29 (bs, 1 H), 6.69 (s, 1 H), 7.48

(m_c, 3 H), 7.81 (s, 1 H), 7.88 (m_c, 3 H), 9.73 (bs, 1 H). HRMS

calcd for C₂₅H₂₈N₃O₃m/z (MH^þ), 418.2125; found, 418.2121.

General Procedure 10 (Mitsunobu Cyclization to Tetra-

hydrochromenoimidazoles). A solution of the corresponding diol

and triphenylphosphine (1.3 to 3.0 equiv) in tetrahydrofuran

was treated with DIAD (1.3 to 3.0 equiv), and the mixture was

stirred for 5 min to 18 h at room temperature. The title

compound was isolated by one of the following workup proce-

dures:

Workup 1. In the course of the reaction a precipitate was

formed and the title compound was isolated by filtration.

Workup 2. The reaction mixture was concentrated in vacuo,

and the crude product was purified by column chromatography

on silica gel and in some cases by crystallization or slurrying in a

suitable solvent.

Workup 3. The reaction mixture was concentrated in vacuo in

the presence of silica gel, and the residue was purified by column

chromatography on silica gel and in some cases by crystal-

lization or slurrying in a suitable solvent.

5-[(3R)-3-(2-Chloro-4-fluorophenyl)-3-hydroxypropyl]-4-hy-

droxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide

(99). The title compound was prepared by asymmetric reduction

of ketone 57 (3 ꢀ 5.0 g, 3 ꢀ 12.0 mmol) as described in general

procedure9: 11.85 g of a slightlygreen solid (79% yield, 84.5% ee).

The optical purity of the title compound was determined by

1

capillary electrophoresis using the method described above. H

Workup 4. The reaction mixture was concentrated in vacuo,

and the residue was dissolved in dichloromethane and ice-water.

A pH value of 2 was adjusted by addition of hydrochloric acid (2

N), and the organic phase was discarded. The aqueous phase was

treated with sodium hydroxide solution (2 N) until a pH value of

10 was obtained and extracted with dichloromethane (3ꢀ). The

combined organic phases were dried over sodium sulfate, and

the solvent was evaporated.

The optical purity of the title compound was determined

either by HPLC (column: Daicel Chiralpak AD-H, 250 mm ꢀ

4.6 mm, 5 μm; flow rate: 1 mL/min; detection wavelength: 218

nm) or by capillary electrophoresis (instrument: Agilent CE-3D;

capillary: Agilent 56/64.5 cm ꢀ 50 μm barefused silica bubble;

buffer: 50 mM sodium phosphate, pH 2.5; chiral selector:

40 mM heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin; voltage:

30 kV; temperature: 20 °C; detection wavelength: 219/226 nm).

(8S)-N,2,3-Trimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazole-5-carboxamide (21). The title com-

pound was prepared by Mitsunobu cyclization of diol 83 (270

mg, 0.73 mmol) as described in general procedure 10 (reaction

time: 18 h). Workup 1; 89 mg of a colorless solid (35% yield,

97.5% ee). HPLC analytical method: eluant, n-heptane/

ethanol = 80:20 (v/v) þ 0.1% diethylamine; t_R(8R) = 6.0 min/

1.3 area %; t_R(8S) = 7.9 min/98.7 area %; mp 259-260 °C. ¹H

NMR (DMSO-d₆, 400 MHz): δ = 1.94 (m_c, 1 H), 2.22 (m_c, 1 H),

2.38 (s, 3 H), 2.47 (s, 3 H), 2.77, 2.83 (d, m_c, 4 H), 3.12 (m_c, 1 H),

NMR (DMSO-d₆, 300 MHz): δ = 1.55-2.10 (m, 2 H), 2.40 (m_c),

2.70 (s, bs, 4 H), 2.91 (s, 3 H), 3.64 (s, 3 H), 4.87 (bt, 1 H), 5.40 (bs,

1 H), 6.71 (s, 1 H), 7.23 (m_c, 1 H), 7.33 (m_c, 1 H), 7.60 (m_c, 1 H),

10.01 (bs, 1 H). HRMS calcd for C₂₁H₂₄ClFN₃O₃m/z (MH^þ),

420.1485; found, 420.1485. Anal. (C₂₁H₂₃ClFN₃O₃): C, H, N.

5-[(3R)-3-(2,4-Dichlorophenyl)-3-hydroxypropyl]-4-hydroxy-

N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (100).

The title compound was prepared by asymmetric reduction of

ketone 58 (6.0 g, 13.8 mmol) as described in general procedure 9:

3.2 g of a colorless solid (53% yield, 69.0% ee). To enhance the

optical purity, a mixture of the title compound (3.0 g, 6.9 mmol)

and ^L-(þ)-mandelic acid (1.26 g, 8.3 mmol) in acetone (60 mL)

was stirred for 1 h at 50 °C and for 18 h at room temperature.

The precipitate was isolated by filtration and the title compound

released by treatment with saturated sodium bicarbonate solu-

tion. A suspension was formed upon addition of dichloro-

methane. The title compound was isolated by filtration,

slurried in water (20 mL), and dried in vacuo (50 °C): 1.9 g,

32% overall yield, ee determined after Mitsunobu cyclization to

117. CE analytical method: t_M(3S) = 25.1 min/15.5 area %; t_M

(3R) = 26.2 min/84.5 area %. ¹H NMR (DMSO-d₆, 200 MHz):

δ = 1.73 (bs, 2 H), 2.45 (bs), 2.69 (bs, 4 H), 2.90 (s, 3 H), 3.64 (s, 3

H), 4.86 (bt, 1 H), 5.44 (bs, 1 H), 6.70 (s, 1 H), 7.43 (m_c, 1 H), 7.51

(m_c, 1 H), 7.58 (m_c, 1 H), 9.80 (bs, 1 H). HRMS calcd for

C₂₁H₂₄Cl₂N₃O₃m/z (MH^þ), 436.1189; found, 436.1185.

3668 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

3.69 (s, 3 H), 5.29 (dd, 1 H), 7.12 (s, 1 H), 7.27 (m_c, 3 H), 7.45 (m_c,

1 H), 8.09 (q, 1 H). HRMS calcd for C₂₁H₂₄N₃O₂m/z (MH^þ),

350.1863; found, 350.1862.

200 MHz): δ = 2.15 (m_c, 4 H), 2.47 (s), 2.74 (m_c, 1 H), 2.96 (m_c, 1

H), 3.69 (s, 3 H), 3.94 (m_c, 4 H), 5.21 (dd, 1 H), 7.03 (s, 1 H), 7.40

(m_c, 5 H). HRMS calcd for C₂₂H₂₄N₃O₂m/z (MH^þ), 362.1863;

found, 362.1857.

(8S)-N-Cyclopropyl-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-

tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (25). The ti-

tle compound was prepared by Mitsunobu cyclization of diol 84

(0.32 g, 0.81 mmol) as described in general procedure 10 (reaction

time: 10 min). Workup 2; eluant for column chromatography:

ethyl acetate, then ethyl acetate/methanol = 9:1 (v/v). Slurrying in

diethyl ether: 200 mg of a colorless solid (66% yield, 97.5% ee).

HPLC analytical method: eluant, n-heptane/ethanol = 80:20 (v/

v); t_R(8R) = 6.0 min/1.2 area %; t_R(8S) = 7.9 min/97.5 area %;

mp 289 °C. ¹H NMR (CDCl₃, 200 MHz): δ = 0.64 (m_c, 2 H), 0.90

(m_c, 2 H), 2.08 (m_c, 1 H), 2.26 (m_c, 1 H), 2.37 (s, 3 H), 2.56 (s, 3 H),

2.98 (m_c, 2 H), 3.22 (m_c, 1 H), 3.68 (s, 3 H), 5.39 (dd, 1 H), 6.02 (bs,

1 H), 6.94 (s, 1 H), 7.19 (m_c, 3 H), 7.56 (m_c, 1 H). HRMS calcd for

C₂₃H₂₆N₃O₂m/z (MH^þ), 376.2020; found, 376.2017.

[(8S)-2,3-Dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazol-5-yl](pyrrolidin-1-yl)methanone Hydrochlo-

ride (39). The title compound (free base) was prepared by

Mitsunobu cyclization of diol 85 (750 mg, 1.8 mmol) as de-

scribed in general procedure 10 (reaction time: 5 h). Workup 2;

eluant for column chromatography: dichloromethane/metha-

nol = 20:1 (v/v). Salt formation by addition of a 2 M solution of

hydrochloric acid in diethyl ether to a solution of the free base of

the title compound in acetone (rt, 17 h, then removal of the

solvent). Crystallization from acetone/diethyl ether: 401 mg of a

beige solid (51% yield, 79.8% ee). HPLC analytical method:

eluant, n-heptane/ethanol = 80:20 (v/v); t_R(8R) = 12.7 min/

10.1 area %; t_R(8S) = 20.0 min/89.9 area %; mp 127-128 °C.

¹H NMR (DMSO-d₆, 400 MHz): δ = 1.92 (m_c, 5 H), 2.21 (m_c, 1

H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.66 (m_c, 1 H), 2.93 (m_c, 1 H), 3.07

(m_c, 1 H), 3.21 (m_c, 1 H), 3.48 (m_c, 2 H), 3.68 (s, 3 H), 5.32 (dd, 1

H), 6.98 (s, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H). HRMS calcd for

C₂₄H₂₈N₃O₂m/z (MH^þ), 390.2176; found, 390.2172.

(8S)-8-(2-Fluorophenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide (107). The title

compound was prepared by Mitsunobu cyclization of diol 90

(1.6 g, 4.1 mmol) as described in general procedure 10 (reaction

time: 1 h). Workup: The reaction mixture was concentrated in

vacuo. The residue was treated with saturated ammonium

chloride solution (100 mL) and extracted with ethyl acetate

(3 ꢀ 100 mL). The combined organic phases were dried over

magnesium sulfate and concentrated in vacuo. The residue was

purified by column chromatography on silica gel [eluant: di-

chloromethane/methanol = 14:1 (v/v)] and crystallized from

acetone to afford 0.8 g (62% yield, 96.1% ee) of the title

compound as a white solid. HPLC analytical method: eluant,

n-heptane/ethanol=80:20 (v/v) þ 0.1% diethylamine; t_R(8R)=

12.4 min/1.9 area %; t_R(8S) = 13.6 min/96.4 area %; mp

199-201 °C. ¹H NMR (DMSO-d₆, 200 MHz): δ = 2.15 (m_c, 2

H), 2.47, 2.55 (s, m_c), 2.79, 2.83 (s, m_c, 4 H), 3.01 (s, 3 H), 3.68 (s,

3 H), 5.44 (dd, 1 H), 6.94 (s, 1 H), 7.27 (t, 2 H), 7.44 (m_c, 1 H),

7.56 (t, 1 H). HRMS calcd for C₂₁H₂₃FN₃O₂m/z (MH^þ),

368.1769; found, 368.1761.

(8S)-8-(2-Chlorophenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide (108). The title

compound was prepared by Mitsunobu cyclization of diol 91

(200 mg, 0.50 mmol) as described in general procedure 10

(reaction time: 5 min). Workup 2; Eluant for column chroma-

tography: dichloromethane/methanol = 100:3 (v/v); 175 mg of

a colorless foam (91% yield, 89.6% ee). HPLC analytical

method: eluant, n-heptane/ethanol = 90:10 (v/v); t_R(8R) = 28.5

1

min/5.2 area %; t_R(8S) = 31.3 min/94.8 area %. H NMR

(DMSO-d₆, 200 MHz): δ = 1.99 (m_c, 1 H), 2.30 (m_c, 1 H), 2.52

(s), 2.64 (bs, 1 H), 2.80, 2.88 (s, m_c, 4 H), 3.01 (s, 3 H), 3.69 (s, 3

H), 5.47 (dd, 1 H), 6.96 (s, 1 H), 7.46 (m_c, 3 H), 7.63 (m_c, 1 H).

HRMS calcd for C₂₁H₂₃ClN₃O₂m/z (MH^þ), 384.1473; found,

384.1472.

(8S)-5-(Methoxymethyl)-2,3-dimethyl-8-(2-methylphenyl)-3,6,

7,8-tetrahydrochromeno[7,8-d]imidazole (43). The title com-

pound was prepared by Mitsunobu cyclization of diol 86 (800

mg, 2.26 mmol) as described in general procedure 10 (reaction

time: 0.5 h). Workup 3; eluant for column chromatography:

first column, ethyl acetate; second column, ethyl acetate/petro-

leum ether = 3:2 (v/v), then ethyl acetate; 600 mg of a colorless

solid (79% yield, 95.4% ee). HPLC analytical method: eluant, n-

hexane/2-propanol = 95:5 (v/v); t_R(8R) = 30.0 min/2.3 area %;

(8S)-8-(2-Ethylphenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazole-5-carboxamide (109). The title com-

pound was prepared by Mitsunobu cyclization of diol 92 (130

mg, 0.33 mmol) as described in general procedure 10 (reaction

time: 5 min). Workup 2; Eluant for column chromatography:

dichloromethane/methanol = 100:3 (v/v); 90 mg of a colorless

foam (73% yield, 83.4% ee). HPLC analytical method: eluant,

n-heptane/ethanol = 80:20 (v/v); t_R(8R) = 8.3 min/8.3 area %;

t_R(8S) = 9.5 min/91.7 area %. ¹H NMR (DMSO-d₆, 200 MHz):

δ = 1.21 (t, 3 H), 1.90-2.30 (m_c, 2 H), 2.46 (s, 3 H), 2.55-2.95,

2.73, 2.82 (m_c, dq, s, 7 H), 3.02 (s, 3 H), 3.67 (s, 3 H), 5.34 (dd, 1

H), 6.92 (s, 1 H), 7.29 (m_c, 3 H), 7.48 (m_c, 1 H). HRMS calcd for

C₂₃H₂₈N₃O₂m/z (MH^þ), 378.2176; found, 378.2173. Anal.

(C₂₃H₂₇N₃O₂): C, H, N.

t

_R(8S) = 37.7 min/97.7 area %. ¹H NMR (DMSO, 200 MHz):

δ = 1.99 (m_c, 1 H), 2.26 (m_c, 1 H), 2.38 (s, 3 H), 2.45 (s, 3 H), 2.94

(m_c, 2 H), 3.33 (s, 3 H), 3.67 (s, 3 H), 4.48 (s, 2 H), 5.24 (dd, 1 H),

7.02 (s, 1 H), 7.27 (m_c, 3 H), 7.49 (m_c, 1 H). HRMS calcd for

C₂₁H₂₅N₂O₂m/z (MH^þ), 337.1911; found, 337.1913. Anal.

(C₂₁H₂₄N₂O₂): H, N. For C: calcd, 74.97; found, 74.24.

(8S)-N,2,3-Trimethyl-8-phenyl-3,6,7,8-tetrahydrochromeno[7,

8-d]imidazole-5-carboxamide (105). The title compound was

prepared by Mitsunobu cyclization of diol 88 (1.0 g, 2.8 mmol)

as described in general procedure 10 (reaction time: 18 h).

Workup 2; eluant for column chromatography: dichloro-

methane/methanol = 10:1 (v/v); 0.79 g of a white solid (75%

yield; 73.2% ee). CE analytical method: t_M(8S) = 22.0 min/86.6

area %; t_M(8R) = 24.4 min/13.4 area %; mp 290-291 °C. ¹H

NMR (DMSO-d₆, 200 MHz): δ = 2.02 (m_c, 1 H), 2.22 (m_c, 1 H),

2.48 (s), 2.76, 2.80 (d, m_c, 4 H), 3.05 (m_c, 1 H), 3.69 (s, 3 H), 5.19

(dd, 1 H), 7.11 (s, 1 H), 7.42 (m_c, 5 H), 8.08 (q, 1 H). HRMS calcd

for C₂₀H₂₂N₃O₂m/z (MH^þ), 336.1707; found, 336.1698. Anal.

(C₂₀H₂₁N₃O₂): H, N. For C: calcd, 71.62; found, 71.21.

(8S)-8-(2-Cyclopropylphenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetra-

hydrochromeno[7,8-d]imidazole-5-carboxamide (110). The title

compound was prepared by Mitsunobu cyclization of diol 93

(3.80 g, 9.4 mmol) as described in general procedure 10 (reaction

time: 30 min). Workup 4 (extraction with ethyl acetate instead of

dichloromethane) and column chromatography [eluant: ethyl

acetate, then ethyl acetate/methanol = 50:1 (v/v)]: 1.9 g of a

colorless foam (53% yield, no separation of enantiomers ac-

1

complished by HPLC). H NMR (DMSO-d₆, 200 MHz): δ =

0.69 (m_c, 2 H), 0.94 (m_c, 2 H), 2.08 (m_c, 2 H), 2.30 (m_c, 1 H), 2.47

(s, 3 H), 2.60 (m_c, 1 H), 2.81 (s, 3 H), 2.92 (m_c, 1 H), 3.02 (s, 3 H),

3.68 (s, 3 H), 5.65 (d, 1 H), 6.93 (s, 1 H), 7.07 (m_c, 1 H), 7.26 (m_c, 2

H), 7.49 (m_c, 1 H). HRMS calcd for C₂₄H₂₈N₃O₂m/z (MH^þ),

390.2176; found, 390.2177.

(8S)-8-[2-(Methoxymethyl)phenyl]-N,N,2,3-tetramethyl-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (111).

The title compound was prepared by Mitsunobu cyclization of

diol 94 (900 mg, 2.19 mmol) as described in general procedure 10

Azetidin-1-yl[(8S)-2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazol-5-yl]methanone (106). The title com-

pound was prepared by Mitsunobu cyclization of diol 89 (0.8

g, 2.2 mmol) as described in general procedure 10 (reaction time:

18 h). Workup 1; 0.6 g of a white solid (76% yield; 81.8% ee). CE

analytical method: t_M(8S) = 21.3 min/90.9 area %; t_M(8R) =

1

23.2 min/9.1 area %; mp 241-242 °C. H NMR (DMSO-d₆,

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3669

(reaction time: 10 min). Workup 2; eluant for column chroma-

tography: dichloromethane/methanol = 20:1 (v/v). Slurrying in

diethyl ether: 430 mg of a colorless solid (50% yield, 98.0% ee).

HPLC analytical method: eluant, n-hexane/2-propanol = 90:10

(v/v); t_R(8R) = 46.1 min/1.0 area %; t_R(8S) = 48.8 min/97.6

area %; mp 200 °C. ¹H NMR (DMSO-d₆, 200 MHz): δ = 1.99

(m_c, 1 H), 2.23 (m_c, 1 H), 2.46 (s, 3 H), 2.64 (m_c, 1 H), 2.81, 2.85

(s, m_c, 4 H), 3.02 (s, 3 H), 3.30 (s), 3.68 (s, 3 H), 4.56 (dd, 2 H),

5.36 (dd, 1 H), 6.93 (s, 1 H), 7.38 (m_c, 3 H), 7.65 (m_c, 1 H).

HRMS calcd for C₂₃H₂₈N₃O₃m/z (MH^þ), 394.2125; found,

394.2123. Anal. (C₂₃H₂₇N₃O₃): C, H, N.

solvent was removed in vacuo. The title compound was purified

further by crystallization from isopropyl acetate and dried in

vacuo at a temperature of 50 °C: 3.43 g of a colorless solid (66%

yield, 95.4% ee). HPLC analytical method: eluant, n-heptane/

ethanol = 80:20 (v/v); t_R(8R) = 13.8 min/2.3 area %; t_R(8S) =

1

19.2 min/97.7 area %. H NMR (DMSO-d₆, 300 MHz): δ =

1.93 (m_c, 1 H), 2.21 (m_c, 1 H), 2.39 (s, 3 H), 2.47 (s, 3 H), 2.62 (m_c,

1 H), 2.80, 2.88 (s, m_c, 4 H), 3.01 (s, 3 H), 3.68 (s, 3 H), 5.32 (d, 1

H), 6.93 (s, 1 H), 7.33 (m_c, 2 H), 7.48 (d, 1 H). HRMS calcd for

C₂₂H₂₅ClN₃O₂m/z (MH^þ), 398.1630; found, 398.1631. Anal.

(C₂₂H₂₄ClN₃O₂): C, H, N.

(8S)-8-(4-Fluorophenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide Hydrochloride

(112). The free base of the title compound was prepared by

Mitsunobu cyclization of diol 95 (1.8 g, 4.7 mmol) as described

in general procedure 10 (reaction time: 3 h). Workup 3; eluant

for column chromatography: dichloromethane/methanol =

100:0 to 87:13 (v/v). Crystallization from acetone and a satu-

rated solution of HCl in diethyl ether: batch 1, 0.81 g of a

colorless solid (43% yield); batch 2, 0.36 g of a colorless solid

(19% yield, 81.8% ee). A batch of the free base of the title

compound was obtained by purification of the mother liquor

[column chromatography on silica gel, eluant: dichloro-

methane/methanol = 20:1 (v/v)]: 0.50 g of a colorless solid

(30% yield). CE analytical method: t_M(8S) = 20.1 min/90.1

(8S)-8-(2-Chloro-4-fluorophenyl)-N,N,2,3-tetramethyl-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (116).

The title compound was prepared by Mitsunobu cyclization of

diol 99 (16.5 g, 39 mmol) as described in general procedure 10

(reaction time: 0.5 h). Workup: The reaction mixture was diluted

with water and a pH value of 3 was adjusted by addition of 2 N

hydrochloric acid (40 mL). The acidic solution was extracted

with ethyl acetate (3ꢀ), and the organic extracts were discarded.

The aqueous phase was treated with concentrated ammonia

solution (20 mL) until a pH value of 9.5 was obtained. A

precipitate was formed which was collected by filtration, washed

with water, and dried in vacuo at temperatures of 50 and 100 °C.

This afforded the pure title compound in 91% yield (14.4 g of a

colorless solid). ¹H NMR (DMSO-d₆, 300 MHz): δ = 1.99 (m_c,

1 H), 2.28 (m_c, 1 H), 2.48 (s, 3 H), 2.63 (m_c, 1 H), 2.80, 2.87 (s, m_c,

4 H), 3.01 (s, 3 H), 3.68 (s, 3 H), 5.43 (dd, 1 H), 6.96 (s, 1 H), 7.34

(m_c, 1 H), 7.53 (m_c, 1 H), 7.66 (m_c, 1 H). HRMS calcd for

C₂₁H₂₂ClFN₃O₂m/z (MH^þ), 402.1379; found, 402.1379.

(8S)-8-(2,4-Dichlorophenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetra-

hydrochromeno[7,8-d]imidazole-5-carboxamide (117). The title

compound was prepared by Mitsunobu cyclization of diol 100

(1.90 g, 4.5 mmol) as described in general procedure 10

(temperature: 60 °C, reaction time: 1 h). Workup: The reaction

mixture was concentrated. The residue was dissolved in ethyl

acetate (50 mL) and 1 N hydrochloric acid (50 mL), and the

phases were separated. The acidic aqueous phase was extracted

with ethyl acetate (3 ꢀ 20 mL), and the organic extracts were

discarded. The aqueous phase was treated with 25% ammonia

solution and extracted with ethyl acetate (2 ꢀ 40 mL). A mixture

of the title compound with inorganic salts (690 mg) precipitated

from the ethyl acetate phase. The solid was treated with di-

chloromethane (30 mL) and water (20 mL). The phases were

separated and the aqueous phase extracted with dichloro-

methane (2 ꢀ 10 mL). The combined organic phases were dried

over magnesium sulfate and concentrated in vacuo: 630 mg of a

colorless solid (34% yield, 95.2% ee). HPLC analytical method:

eluant, n-heptane/ethanol = 80:20 (v/v); t_R(8R) = 14.0 min/2.4

area %; t_R(8S) = 20.1 min/97.6 area %. ¹H NMR (DMSO-d₆,

400 MHz): δ = 1.96 (m_c, 1 H), 2.29 (m_c, 1 H), 2.48 (s), 2.62 (m_c, 1

H), 2.79, 2.84 (s, m_c, 4 H), 3.01 (s, 3 H), 3.69 (s, 3 H), 5.44 (d, 1

H), 6.98 (s, 1 H), 7.55 (m_c, 1 H), 7.63 (m_c, 1 H), 7.71 (m_c, 1 H).

HRMS calcd for C₂₁H₂₂Cl₂N₃O₂m/z (MH^þ), 418.1084; found,

418.1086.

1

area %; t_M(8R) = 21.0 min/9.0 area %; mp 290-292 °C. H

NMR (DMSO-d₆, 200 MHz): δ = 2.13 (m_c, 1 H), 2.33 (m_c, 1 H),

2.75, 2.77, 2.79 (m_c, 2 s, 8 H), 3.04 (s, 3 H), 3.89 (s, 3 H), 5.42 (dd,

1 H), 7.28 (t, 2 H), 7.41 (s, 1 H), 7.62 (dd, 2 H). HRMS calcd for

C₂₁H₂₃FN₃O₂m/z (MH^þ), 368.1796; found, 368.1796.

(8S)-8-(4-Chlorophenyl)-N,N,2,3-tetramethyl-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide (113). The title

compound was prepared by Mitsunobu cyclization of diol 96

(11.6 g, 28.9 mmol) as described in general procedure 10

(reaction time: 1.5 h). Work up 4 and slurrying in isopropyl

acetate (30 mL): 9.4 g of a colorless solid (85% yield, 60.0% ee).

HPLC analytical method: eluant, n-heptane/ethanol = 70:30

(v/v); t_R(8R) = 13.2 min/20.0 area %; t_R(8S) = 19.1 min/80.0

area %; mp 234-236 °C. ¹H NMR (DMSO-d₆, 200 MHz): δ =

2.03 (m_c, 1 H), 2.24 (m_c, 1 H), 2.48, 2.50 (s, m_c), 2.76 (s, m_c, 4 H),

3.00 (s, 3 H), 3.68 (s, 3 H), 5.25 (dd, 1 H), 6.93 (s, 1 H), 7.49 (m_c, 4

H). HRMS calcd for C₂₁H₂₃ClN₃O₂m/z (MH^þ), 384.1473;

found, 384.1474. Anal. (C₂₁H₂₂ClN₃O₂): H, N, Cl. For C: calcd,

65.71; found, 65.09.

(8S)-8-(4-Fluoro-2-methylphenyl)-N,N,2,3-tetramethyl-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (114).

The title compound was prepared by Mitsunobu cyclization of

diol 97 (630 mg, 1.58 mmol) as described in general procedure 10

(reaction time: 30 min). Workup 2; eluant for column chroma-

tography: dichloromethane/methanol = 100:3 (v/v); 290 mg of

a colorless foam (48% yield, 83.0% ee). HPLC analytical

method: eluant, n-heptane/ethanol = 80:20 (v/v); t_R(8R) =

12.4 min/8.5 area %; t_R(8S) = 17.5 min/91.5 area %. ¹H NMR

(DMSO-d₆, 200 MHz): δ = 1.99 (m_c, 1 H), 2.21 (m_c, 1 H), 2.40

(s, 3 H), 2.47 (s, 3 H), 2.57-2.74 (m, 1 H), 2.74-2.96, 2.80 (m, s, 4

H), 3.02 (s, 3 H), 3.68 (s, 3 H), 5.30 (dd, 1 H), 6.93 (s, 1 H), 7.09

(m_c, 2 H), 7.49 (m_c, 1 H). HRMS calcd for C₂₂H₂₅FN₃O₂m/z

(MH^þ), 382.1925; found, 382.1928.

(8S)-8-(4-Chloro-2-methylphenyl)-N,N,2,3-tetramethyl-3,6,7,

8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (115).

The title compound was prepared by Mitsunobu cyclization of

diol 98 (5.4 g, 13.0 mmol) as described in general procedure 10

(reaction time: 18 h). The reaction solvent was removed in vacuo

and the residue distributed between ethyl acetate and 1 N

hydrochloric acid. The phases were separated and the aqueous

phase extracted with ethyl acetate (3ꢀ) and dichloromethane

(1ꢀ). The organic extracts were discarded. A basic pH value was

adjusted by addition of 25% aqueous ammonia solution and the

aqueous phase extracted with ethyl acetate (2ꢀ). The combined

organic phases were dried over magnesium sulfate, and the

(8S)-N,N,2,3-Tetramethyl-8-(naphthalen-2-yl)-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide hydrochloride (118).

The title compound (free base) was prepared by Mitsunobu

cyclization of diol 101 (150 mg, 0.36 mmol) as described in

general procedure 10 (reaction time: 4.25 h). Workup 2; eluant

for column chromatography: dichloromethane/methanol = 20:1

(v/v). Salt formation by addition of a 2 M solution of hydro-

chloric acidindiethyl ethertoa solutionofthe free base of the title

compound in acetone. The precipitate was isolated by filtration

and dried in vacuo: 101 mg of a beige solid (64% yield, 38.6% ee).

HPLC analytical method: eluant, n-heptane/ethanol = 80:20 (v/

v) þ 0.1% diethylamine; t_R(8R) = 25.3 min/30.4 area %; t_R

(8S) = 31.2 min/68.7 area %; mp 262-264 °C. ¹H NMR

(DMSO-d₆, 200 MHz): δ = 2.25 (m_c, 1 H), 2.45 (m_c), 2.72,

2.78, 2.81 (m_c, s, s, 7 H), 3.01, 3.05 (m_c, s, 4 H), 3.90 (s, 3 H), 5.59

(dd, 1H), 7.43(s, 1H), 7.56(m_c, 2H), 7.70(m_c, 1H), 7.99(m_c, 3H),

3670 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

8.14 (s, 1 H). HRMS calcd for C₂₅H₂₆N₃O₂m/z (MH^þ),

400.2020; found, 400.2021.

acetate (2 ꢀ 20 mL). The combined organic phases were washed

with water (2 ꢀ 30 mL), dried over sodium sulfate, and

concentrated under reduced pressure. The residue was purified

by column chromatography [200 g of silica gel, eluant: dichlor-

omethane, then dichloromethane/methanol = 100:1 (v/v)] and

crystallization from diethyl ether (30 mL). The title compound

was isolated by filtration, washed with diethyl ether (15 mL),

and dried in vacuo: 2.8 g of a colorless solid (51% yield); mp

122-124 °C. ¹H NMR (DMSO-d₆, 300 MHz): δ = 1.09 (d, 4 H),

2.24 (quintet, 1 H), 2.36 (s, 3 H), 2.63, 2.73 (bs, s, 4 H), 2.92, 2.99

(bs, s, 6 H), 3.81 (s, 3 H), 5.75 (s, 2 H), 7.00 (s, 1 H), 7.24 (m_c, 5

H), 7.39 (m_c, 3 H), 7.54 (m_c, 1 H). HRMS calcd for C₃₁H₃₄N₃O₃

m/z (MH^þ), 496.2595; found, 496.2594. Anal. (C₃₁H₃₃N₃O₃): C,

H, N.

4-(Benzyloxy)-2-cyclopropyl-5-[(3R)-3-hydroxy-3-(2-methyl-

phenyl)propyl]-N,N,1-trimethyl-1H-benzimidazole-6-carboxamide

(136). In a 100 mL autoclave, the protected ketone 135 (3.0 g, 6.0

mmol) was dissolved in dry 2-propanol (40 mL). Potassium tert-

butylate (0.6 mL of a 1 M solution in tert-butanol, 0.6 mmol)

and the hydrogenation catalyst RuCl₂[(S)-Xyl-P-Phos][(S)-

DAIPEN] 82 (8 mg, S/C = 1000:1) were added. The reactor

was purged with hydrogen (3ꢀ) and subjected to a hydrogen

pressure of 80 bar. The hydrogenation was conducted at 70 °C

over a period of 17 h. After cooling to room temperature and

release of the hydrogen pressure, the reaction mixture was

poured on saturated ammonium chloride solution (70 mL)

and dichloromethane (130 mL). The phases were separated,

and the aqueous phase was extracted with dichloromethane (2 ꢀ

20 mL). The combined organic phases were washed with water

(2 ꢀ 30 mL), dried over sodium sulfate, and concentrated under

reduced pressure. The residue (3.0 g of a foamy solid, 95.0% ee)

was purified by column chromatography [100 g of silica gel,

eluant: dichloromethane/methanol = 100:2 (v/v)]: 2.8 g of a

colorless solid (90% yield, 95.4% ee). HPLC analytical method:

column, Daicel Chiralcel OD-H, 250 mm ꢀ 4.6 mm, 5 μm; flow

rate, 1 mL/min; detection wavelength, 218 nm; eluant, n-hep-

tane/ethanol = 90:10 (v/v); t_R(3R) = 12.4 min/97.7 area %; t_R

(3S) = 14.0 min/2.3 area %; mp 109-111 °C. ¹H NMR

(DMSO-d₆, 400 MHz): δ = 1.08 (d, 4 H), 1.60 (bs, 1 H), 1.79

(bs, 1 H), 2.18 (s, 3 H), 2.24 (quintet, 1 H), 2.55 (bs), 2.66 (s, 3 H),

2.88, 2.93 (bs, s, 4 H), 3.78 (s, 3 H), 4.68 (bs, 1 H), 4.97 (bs, 1 H),

5.67 (s, 2 H), 6.93 (s, 1 H), 7.12 (m_c, 3 H), 7.31 (m_c, 3 H), 7.40 (m_c,

3 H). HRMS calcd for C₃₁H₃₆N₃O₃m/z (MH^þ), 498.2751;

found, 498.2752.

2-Cyclopropyl-4-hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)-

propyl]-N,N,1-trimethyl-1H-benzimidazole-6-carboxamide (137).

Palladium on charcoal (0.3 g, 10 wt %) was added to a solution

of the benzyl-protected alcohol 136 (2.7 g, 5.4 mmol) in dry

ethanol (80 mL). The reaction mixture was hydrogenated (1 bar

hydrogen pressure) at room temperature for 18 h. The catalyst

was removed by filtration and washed with dichloromethane.

Evaporation of the combined filtrates afforded the title com-

pound: 2.1 g of a colorless solid (95% yield, 95.9% ee). HPLC

analytical method: column, Daicel Chiralpak AD-H, 250 mm ꢀ

4.6 mm, 5 μm; flow rate, 1 mL/min; detection wavelength, 218

nm; eluant, n-heptane/ethanol = 85:15 (v/v); t_R(3R) = 17.7 min/

91.3 area %; t_R(3S) = 21.3 min/1.9 area %; mp 148-150 °C. ¹H

NMR (DMSO-d₆, 300 MHz): δ = 1.05 (d, 4 H), 1.72 (bs, 2 H),

2.19, 2.22 (m_c, s, 4 H), 2.55 (bs), 2.69 (s, 3 H), 2.85, 2.92 (m_c, s, 4

H), 3.76 (s, 3 H), 4.69 (bs, 1 H), 5.03 (bs, 1 H), 6.71 (s, 1 H), 7.08

(m_c, 2 H), 7.15 (m_c, 1 H), 7.40 (m_c, 1 H), 9.43 (bs, 1 H). HRMS

calcd for C₂₄H₃₀N₃O₃m/z (MH^þ), 408.2282; found, 408.2271.

(8S)-2-Cyclopropyl-N,N,3-trimethyl-8-(2-methylphenyl)-3,6,

7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide Butane-

dioate (139). DIAD (1.6 g, 6.0 mmol) was added dropwise to a

solution of the diol 137 (1.9 g, 4.6 mmol) and triphenylpho-

sphine (1.6 g, 6.0 mmol) in THF (40 mL). The reaction solution

was stirred for 30 min at room temperature and poured on

saturated ammonium chloride solution (30 mL) and ethyl

acetate (60 mL). The phases were separated, and the aqueous

(8S)-N,N,2,3-Tetramethyl-8-(thiophen-2-yl)-3,6,7,8-tetrahy-

drochromeno[7,8-d]imidazole-5-carboxamide (119). The title

compound was prepared by Mitsunobu cyclization of diol 102

(450 mg, 1.20 mmol) as described in general procedure 10

(reaction time: 0.75 h). Workup 3; eluant for column chroma-

tography: dichloromethane/methanol = 30:1 (v/v); 260 mg of a

colorless foam (61% yield, 77.2% ee). HPLC analytical method:

eluant, n-hexane/2-propanol = 80:20 (v/v); t_R(8S) = 12.3 min/

81.5 area %; t_R(8R) = 16.9 min/10.5 area %.; ¹H NMR

(DMSO-d₆, 400 MHz): δ = 2.16 (m_c, 1 H), 2.35 (m_c, 1 H),

2.47 (s, 3 H), 2.65 (m_c, 1 H), 2.76, 2.79 (s, m_c, 4 H), 3.01 (s, 3 H),

3.67 (s, 3 H), 5.50 (dd, 1 H), 6.92 (s, 1 H), 7.07 (m_c, 1 H), 7.20 (m_c,

1 H), 7.55 (m_c, 1 H). HRMS calcd for C₁₉H₂₂N₃O₂S m/z (MH^þ),

356.1427; found, 356.1428.

(8S)-N,N,2,3-Tetramethyl-8-(2-methylthiophen-3-yl)-3,6,7,8-

tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (120). The

title compound was prepared by Mitsunobu cyclization of diol

103 (0.54 g, 1.4 mmol) as described in general procedure 10

(reaction time: 10 min). Workup 2; eluant for column chroma-

tography: ethyl acetate, then ethyl acetate/methanol = 9:1 (v/v).

Slurrying in diethyl ether: 200 mg of a colorless solid (39%

yield); Mp 233 °C. ¹H NMR (DMSO-d₆, 200 MHz): δ = 2.20

(m_c, 2 H), 2.47 (s, 3 H), 2.57 (s, 3 H), 2.88 (s, bs, 5 H), 3.15 (s, 3

H), 3.67 (s, 3 H), 5.27 (dd, 1 H), 6.76 (s, 1 H), 7.03 (m_c, 2 H).

HRMS calcd for C₂₀H₂₄N₃O₂S m/z (MH^þ), 370.1584; found,

370.1578. Anal. (C₂₀H₂₃N₃O₂S): C, H, N.

5.1.5. Variation of the Substituents Attached to the Imidazole

Part of the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole Scaf-

fold. 2-Cyclopropyl-4-hydroxy-N,N,1-trimethyl-5-[3-(2-methyl-

phenyl)-3-oxopropyl]-1H-benzimidazole-6-carboxamide (134).

At a temperature of 60 °C, potassium tert-pentylate (42.0 mL of

a 25% solution in toluene diluted with 22 mL of dry DMF) was

added over a period of 40 min to a suspension of the Mannich

base 132 (14.0 g, 31.5 mmol) and ethyl 3-(2-methylphenyl)-3-

oxopropanoate (8.0 g, 40.0 mmol) in dry toluene (120 mL). The

reaction mixture was stirred for 5 h at 60 °C, cooled, and poured

on a mixture of saturated ammonium chloride solution (160

mL) and ethyl acetate (350 mL). The phases were separated and

the aqueous phase extracted with ethyl acetate (40 mL). The

combined organic phases were washed with water (2 ꢀ 40 mL),

dried over sodium sulfate, and concentrated under reduced

pressure. The residue was purified by column chromatography

[220 g of silica gel, eluant: dichloromethane, then dichloro-

methane/methanol = 100:2 (v/v)]. A solution of the resulting

ketoester 133 (6.2 g, 13.0 mmol) in methanol (100 mL) was

heated to 85 °C and treated with cesium carbonate (21.0 g, 65.0

mmol, dissolved in 30 mL of water). After a period of 4 h at 85

°C, the reaction mixture was poured on a mixture of saturated

ammonium chloride solution (100 mL) and dichloromethane

(250 mL). The phases were separated, and the aqueous phase

was extracted with dichloromethane (30 mL). The combined

organic phases were washed with water (40 mL), dried over

sodium sulfate, and concentrated under reduced pressure.

This afforded 4.7 g of the crude title compound (37% yield,

HPLC purity: 88%). ¹H NMR (DMSO-d₆, 300 MHz):

δ = 1.06 (d, 4 H), 2.21 (quintet, 1 H), 2.41 (s, 3 H), 2.77 (s, bs,

4 H), 2.99, 3.03 (s, bs, 6 H), 3.78 (s, 3 H), 6.78 (s, 1 H), 7.30 (m_c, 2

H), 7.42 (m_c, 1 H), 7.68 (m_c, 1 H), 9.62 (bs, 1 H). HRMS calcd for

C₂₄H₂₈N₃O₃m/z (MH^þ), 406.2125; found, 406.2119.

4-(Benzyloxy)-2-cyclopropyl-N,N,1-trimethyl-5-[3-(2-methyl-

phenyl)-3-oxopropyl]-1H-benzimidazole-6-carboxamide (135).

Benzyl bromide (2.4 g, 14.0 mmol) was added dropwise to a

suspension of ketone 134 (4.5 g, 11.0 mmol) and potassium

carbonate (2.0 g, 14.0 mmol) in DMF (70 mL). The reaction

mixture was heated to 55 °C, stirred for 4 h at this temperature,

and poured on a mixture of saturated ammonium chloride

solution (70 mL) and ethyl acetate (180 mL). The phases were

separated and the aqueous phase was extracted with ethyl

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3671

phase was extracted with ethyl acetate (2 ꢀ 15 mL). The com-

bined organic phases were washed with water (2 ꢀ 20 mL), dried

over sodium sulfate, and concentrated under reduced pressure.

The residue (5.0 g of a green oil) was purified by column

chromatography twice [first column, 100 g of silica gel; eluant,

ethyl acetate/methanol = 20:1 (v/v); second column, 50 g of

silica gel; eluant, ethyl acetate/methanol = 100:1 (v/v)]. The free

base of the title compound 138 (1.25 g) was dissolved in methyl

isobutyl ketone (10 mL), and succinic acid (480 mg, 4.0 mmol)

was added. The suspension was stirred for 45 min at 80 °C and

for 17 h at room temperature. The title compound was isolated

by filtration, washed with methyl isobutyl ketone (3 mL), and

dried in vacuo (50 °C): 1.2 g (74% yield, ratio API/succinic

acid = 1:1.5, 95.6% ee). HPLC analytical method: column,

Daicel Chiralpak AD-H, 250 mm ꢀ 4.6 mm, 5 μm; flow rate, 1

mL/min; detection wavelength, 218 nm; eluant, n-heptane/etha-

nol = 80:20 (v/v); t_R(8R) = 9.8 min/2.2 area %; t_R(8S) = 12.8

and extracted with dichloromethane (3ꢀ). The combined organic

layers were dried over magnesium sulfate and concentrated in

vacuo. The residue was purified by column chromatography on

silica gel [eluant: toluene/dioxane = 9:1 (v/v)], affording 19.5 g

(39% yield) of the title compound as a white solid; mp 94-95 °C.

¹H NMR (DMSO-d₆, 400 MHz): δ = -0.10 (s, 9 H), 0.83 (t, 2

H), 2.50 (s, 3 H), 3.47 (t, 2 H), 5.28 (s, 2 H), 5.47 (s, 2 H), 6.90 (s, 1

H), 7.28 (m_c, 1 H), 7.34 (m_c, 2 H), 7.42 (m_c, 3 H). HRMS calcd

for C₂₁H₂₈N₂O₂BrSi m/z (MH^þ), 447.1098; found, 447.1108.

4-(Benzyloxy)-N,N,2-trimethyl-1-{[2-(trimethylsilyl)ethoxy]-

methyl}-1H-benzimidazole-6-carboxamide (145). The bromo de-

rivative 144 (19.5 g, 43.6 mmol), triphenylphosphine (4.6 g, 17.9

mmol), palladium(II) acetate (1.5 g, 6.5 mmol), and dimethyla-

mine solution (2 M in THF, 218 mL, 436 mmol) were transferred

to an autoclave and carbonylated (6 bar CO) for 60 h at 120 °C.

The catalyst was filtered off and the filtrate concentrated in

vacuo. The residue was purified by column chromatography on

silica gel [eluant: toluene/dioxane = 2:1 (v/v)], affording 13.8 g

(72% yield) of the title compound as a white solid; mp 118-120

°C. ¹H NMR (DMSO-d₆, 200 MHz): δ = -0.10 (s, 9 H), 0.81 (t,

2 H), 2.55 (s, 3 H), 2.90 (s, 6 H), 3.50 (t, 2 H), 5.30 (s, 2 H), 5.59 (s,

2 H), 6.80 (s, 1 H), 7.38 (m_c, 6 H). HRMS calcd for C₂₄H₃₄N₃O_3-

Si m/z (MH^þ), 440.2364; found, 440.2371.

1

min/97.8 area %; mp 146-148 °C. H NMR (DMSO-d₆, 300

MHz): δ = 0.99 (m_c, 4 H), 2.00 (m_c, 1 H), 2.18 (m_c, 2 H), 2.37 (s,

3 H), 2.42 (s, 6 H), 2.61 (m_c, 1 H), 2.80, 2.88 (s, bs, 4 H), 3.01 (s, 3

H), 3.79 (s, 3 H), 5.30 (dd, 1 H), 6.92 (s, 1 H), 7.25 (m_c, 3 H), 7.44

(m_c, 1 H), 12.13 (bs, 3 H). HRMS calcd for C₂₄H₂₈N₃O₂m/z

(MH^þ), 390.2176; found, 390.2184.

(8S)-2-(Chloromethyl)-N,N,3-trimethyl-8-(2-methylphenyl)-3,

6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (141).

A solution of alcohol 140 (450 mg, 1.2 mmol) in dichloro-

methane (15 mL) was cooled to 0 °C, and thionyl chloride

(180 mg, 1.5 mmol) was added dropwise. The reaction mixture

was stirred for 2 h at room temperature and poured on a cold

mixture of aqueous sodium carbonate solution (15 mL) and

dichloromethane (10 mL). The phases were separated, and the

aqueous phase was extracted with dichloromethane (10 mL).

The combined organic phases were washed with water (20 mL),

dried over sodium sulfate, and concentrated under reduced

pressure. The title compound (480 mg of a colorless solid,

98% yield) was subjected to the next step without further

purification. ¹H NMR (DMSO-d₆, 300 MHz): δ = 2.03 (m_c, 1

H), 2.27 (m_c, 1 H), 2.40 (s, 3 H), 2.67 (m_c, 1 H), 2.83 (s, 3 H), 2.99,

3.04 (m_c, s, 4 H), 3.89 (s, 3 H), 5.11 (s, 2 H), 5.42 (d, 1 H), 7.18 (s, 1

H), 7.28 (m_c, 3 H), 7.49 (m_c, 1 H). HRMS calcd for

C₂₂H₂₅N₃O₂Cl m/z (MH^þ), 398.1630; found, 398.1628.

(8S)-2-(Methoxymethyl)-N,N,3-trimethyl-8-(2-methylphenyl)-

3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (142).

Sodium methylate (3 mL of a 0.5 M solution in methanol) was

added portionwise to a solution of the chloro derivative 141 (400

mg, 1.0 mmol) in methanol (10 mL). The reaction mixture was

stirred at room temperature for 1 h and heated to 65 °C for 17 h.

After cooling to room temperature, the reaction mixture was

poured on saturated ammonium chloride solution (15 mL) and

dichloromethane (25 mL). The phases were separated, and the

aqueous phase was extracted with dichloromethane (2 ꢀ 10

mL). The combined organic phases were washed with water (2 ꢀ

10 mL), dried over sodium sulfate, and concentrated under

reduced pressure. The residue was crystallized from a mixture

of acetone (1 mL) and diethyl ether (10 mL). The title compound

was isolated by filtration, washed with diethyl ether (5 mL), and

dried in vacuo: 180 mg of a colorless solid, 45% yield; mp

178-180 °C.¹H NMR (DMSO-d₆, 300 MHz): δ = 2.01 (m_c, 1

H), 2.23 (m_c, 1 H), 2.39 (s, 3 H), 2.62 (m_c, 1 H), 2.82, 2.90 (s, bs, 4

H), 3.02 (s, 3 H), 3.29 (s), 3.76 (s, 3 H), 4.64 (s, 2 H), 5.35 (dd, 1

H), 7.00 (s, 1 H), 7.26 (m_c, 3 H), 7.48 (m_c, 1 H). HRMS calcd for

C₂₃H₂₈N₃O₃m/z (MH^þ), 394.2125; found, 394.2125. Anal.

(C₂₃H₂₇N₃O₃): C, H, N.

4-Hydroxy-N,N,2-trimethyl-1-{[2-(trimethylsilyl)ethoxy]me-

thyl}-1H-benzimidazole-6-carboxamide (146). A solution of the

benzyl protected benzimidazole 145 (13.7 g, 31.1 mmol) in

ethanol (1.2 L) was hydrogenated over 10% Pd/C (1.4 g) in an

autoclave (5 bar H₂) for 16 h at room temperature. The catalyst

was filtered off and the filtrate concentrated in vacuo. The

residue was crystallized from diisopropyl ether to afford 10.1 g

(93% yield) of the title compound as a white solid; mp 154-156

°C. ¹H NMR (DMSO-d₆, 200 MHz): δ = -0.11 (s, 9 H), 0.80 (t,

2 H), 2.52 (s, 3 H), 2.93 (s, 6 H), 3.50 (t, 2 H), 5.55 (s, 2 H), 6.55 (s,

1 H), 7.10 (s, 1 H), 9.92 (bs, 1 H). HRMS calcd for C₁₇H₂₈N₃O_3-

Si m/z (MH^þ), 350.1894; found, 350.1894.

4-Hydroxy-N,N,2-trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-

1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carbo-

xamide (147). A solution of the hydroxybenzimidazole 146 (2.4

g, 6.9 mmol) in dichloromethane (40 mL) was treated with

Eschenmoser’s salt (1.8 g, 9.8 mmol), and the reaction was

stirred for 7 h at room temperature. The reaction mixture was

poured into saturated sodium hydrogencarbonate solution,

stirred for 30 min at room temperature, and extracted with

dichloromethane (3ꢀ). The organic layers were dried over

magnesium sulfate and concentrated in vacuo. A suspendion

of the residue (2.77 g of a beige solid, 6.8 mmol, 99% yield) in

1,2-dimethoxyethane (100 mL) was heated to 85 °C, and a

solution of 1-[1-(2-methylphenyl)vinyl]pyrrolidine (2.0 g, 10.7

mmol) was slowly added. The reaction mixture was heated at 85

°C for 3 h, cooled to room temperature, and the solvent was

evaporated in vacuo. A column filled with silica gel was loaded

with the residue, and the title compound was eluted with a

mixture of toluene/1,4-dioxane = 2:1 (v/v). Evaporation of the

corresponding fractions afforded a beige solid that was recrys-

tallized from isopropanol. The title compound was obtained in

20% yield (0.67 g of a colorless solid); mp 163-164 °C. ¹H NMR

(DMSO-d₆, 400 MHz): δ = -0.10 (s, 9 H), 0.83 (t, 2 H), 2.40 (s, 3

H), 2.56 (s, bs, 4 H), 2.75 (s, 3 H), 3.00, 3.05 (s, bs, 6 H), 3.52 (t, 2

H), 5.50 (s, 2 H), 6.90 (s, 1 H), 7.29 (m_c, 2 H), 7.40 (m_c, 1 H), 7.70

(m_c, 1 H), 9.99 (s, 1 H). HRMS calcd for C₂₇H₃₈N₃O₄Si m/z

(MH^þ), 496.2626; found, 496.2623.

4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-N,

N,2-trimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimi-

dazole-6-carboxamide (148). Two samples of ketone 147 (223

mg, 0.45 mmol/271 mg, 0.54 mmol) and RuCl₂[(S)-Xyl-P-Phos]-

[(S)-DAIPEN] 82 (S/C =100:1) were weighed in glass liners

that were then placed in an Argonaut Endeavor (eight wells

pressure parallel reactor, overhead stirrers, and heating block).

The vessel was sealed and the wells purged by pressurizing five

times with nitrogen to 2 bar and releasing the pressure. The base

4-(Benzyloxy)-6-bromo-2-methyl-1-{[2-(trimethylsilyl)ethoxy]-

methyl}-1H-benzimidazole (144). To a suspension of benzimi-

dazole 143 (36.5 g, 115 mmol) and triethylamine (17.7 mL, 138

mmol) in a dimethylformamide-dichloromethane mixture

(10:1) was added dropwise [2-(chloromethoxy)ethyl](trimethyl)-

silane (24.5 mL, 138 mmol) and the suspension was stirred for 5 h at

room temperature. The reaction mixture was poured into water

3672 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9

Palmer et al.

(0.5 mL/0.6 mL of a 1 M solution of potassium tert-butylate in tert-

butanol) and 2-propanol (2.0 mL/2.4 mL) were then injected. The

wells were purged by pressurizing five times with hydrogen to 25 bar

(under stirring) and releasing the pressure. The reaction was then

heated to 65 °C and pressurized to 25 bar of hydrogen. After a period

of 16 h, the hydrogen pressure was released, and the reaction mixtures

were transferred to round bottomed flasks with the help of methanol

(10 mL). The solvent was evaporated, and the crude products were

analyzed by HPLC (both samples: 100% conversion, 91-92% ee).

The combined samples were dissolved in dichloromethane and

washed with saturated ammonium chloride solution. The aqueous

phase was extracted several times with dichloromethane. The com-

bined organic layers were dried over sodium sulfate and concentrated

in vacuo furnishing a green solid (390 mg). A part of the crude

product (350 mg) was purified by column chromatography on silica

gel [eluant: dichloromethane/methanol = 20:1 (v/v)]. This afforded

the pure title compound (320 mg of a foamy solid, 64% yield, 70%

corrected yield, 95.8% ee). Determination of the optical purity

by capillary electrophoresis: instrument, Agilent CE-3D; capillary,

Agilent 56/64.5 cm ꢀ 50 μm bare fused silica bubble; buffer, 50 mM

sodium phosphate, pH 2.5; chiral selector, 40 mM heptakis(2,3,6-tri-

O-methyl)-β-cyclodextrin; voltage, 30 kV; temperature, 20 °C; detec-

tion wavelength, 219 nm; t_M(3S) = 27.5 min/2.1 area %; t_M(3R) =

27.9 min/97.9 area %. ¹H NMR (DMSO-d₆, 400 MHz): δ = -0.10

(s, 9 H), 0.82 (t, 2 H), 1.78 (bm, 2 H), 2.21 (s, 3 H), 2.55 (s), 2.69 (s, 3

H), 2.92 (s, 4 H), 3.50 (t, 2 H), 4.69 (bs, 1 H), 5.03 (bd, 1 H), 5.50 (s, 2

H),6.84(s,1H),7.13(m_c,3H),7.41(m_c,1H),9.77(bs,1H).HRMS

calcd for C₂₇H₄₀N₃O₄Si m/z (MH^þ), 498.2783; found, 498.2789.

(8S)-N,N,2-Trimethyl-8-(2-methylphenyl)-3-{[2-(trimethylsi-

lyl)ethoxy]methyl}-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-

5-carboxamide (149). To a solution of the diol 148 (300 mg, 0.60

mmol) in tetrahydrofuran (10 mL) was added triphenylpho-

sphine (300 mg, 1.14 mmol) and DIAD (240 μL, 245 mg, 1.21

mmol) and the solution was stirred for 10 min at room tem-

perature. The reaction mixture was concentrated in vacuo and

the crude product purified by column chromatography [eluant

for first column,: dichloromethane/methanol = 40:1 (v/v);

eluant for second column, petroleum ether/ethyl acetate = 1:1

to 1:3 (v/v)]. Evaporation of the corresponding fractions af-

forded 430 mg of a mixture of the title compound (30 wt %, 45%

isolated from hog gastric mucosa, reduction of the accumula-

tion of the weak base ¹⁴C-dimethylaminopyridine in intact

gastric glands) and the pharmacological tests (reduction of the

acid output in the Ghosh Schild rat, efficacy and duration of the

antisecretory activity in the fasted fistula dog) have been de-

scribed previously.^5,13,36

5.3. Effect of a Test Compound on the hERG Tail Current

Amplitude in Stably Transfected CHO-K1 Cells Using Patch

Clamp Recordings. CHO-K1 cells stably expressing the hERG

channel (NMI TT GmbH, Reutlingen, Germany) were con-

tinuously maintained and passaged in sterile culture flasks

containing DMEM/ HAM F12 þ 10% FCS (Invitrogen, Karls-

ruhe, Germany) with Zeocin (50 μg/mL, Invitrogen, Karlsruhe,

Germany) to select for cells transfected with the plasmid con-

taining hERG and Zeocin resistance. For electrophysiological

measurements, CHO-K1 cells were seeded onto 12 mm sterile

coverslips positioned in 24-well plates containing 0.5 mL of

culture medium DMEM/ HAM F12 þ 10% FCS at a density of

30000 cells per coverslip. By using this cell density, the cells do

not tend to cluster and are not electrically coupled. The medium

contained Nocodazol (90 ng/mL, Invitrogen, Karlsruhe,

Germany) to arrest the cell cycle in order to generate a poly-

ploide genome. Penicillin/streptomycin (10 μL/ml, Invitrogen,

Karlsruhe, Germany) solution was added to the medium. The

cells were incubated at 37 °C in a humidified atmosphere with

5% CO₂. Test compounds were dissolved in DMSO to prepare

stock solution (in general 1000ꢀ of highest final concentration).

The final concentration (10 μM, adjusted to 0.1% DMSO) was

diluted from the corresponding stock solution shortly prior to

the electrophysiological experiments. The extracellular solution

was prepared freshly every day and kept at room temperature

(19-26 °C). The components of the extracellular solution with

an osmolarity of 300-305 mOsm/kg were (in mM): 140 NaCl, 4

KCl, 4 MgSO₄, 1.8 CaCl₂, 10 HEPES, and 20 glucose. The pH of

the extracellular solution was set to 7.4 using NaOH. The

intracellular solution was thawed every day from a frozen

(-22 °C) aliquot. When in use, the pipet solution was filled into

the patch pipettes. The pipet solution with an osmolarity of

290-295 mOsm/kg included the following components (in

mM): 115 K-Aspartat, 3 MgCl₂, 0.7 CaCl₂, 10 HEPES, 12

EGTA, and 5 K₂-ATP. The pH of the intracellular solution

was set to 7.2 using KOH. CHO-K1 cells were placed on the dish

holder of the microscope and were continuously perfused (at

approximately 2 mL/min). A patch clamp amplifier EPC-10

(HEKA, Lambrecht, Germany) connected to a PC using the

software Pulse v8.79 (HEKA, Lambrecht, Germany) was used

to perform the experiments. Patch electrodes with a pipet

resistance ranging from 2 to 5 MΩ were used to form a gigaseal

between the patch electrode and individual CHO-K1 cells (seal

resistance: > 1 GΩ). The cell membrane under the pipet tip was

then ruptured by negative pressure to ensure electrical access to

the cell interior (whole-cell configuration). With a leak current

larger than 300 pA, the cell was omitted. As soon as a stable seal

was established, a voltage protocol was run every 25 s (start-to-

start). This voltage protocol consisted of a hyperpolarizing step

from -80 to -90 mV to calculate for the membrane resistance,

followed by the repolarization to the holding potential of -80

mV. The hERG outward tail currents were measured upon

depolarization of the membrane potential to þ20 mV for 2750

ms (activation of channels) and subsequent repolarization to

-50 mV for 250 ms. A variation of current amplitudes less than

5% was defined as steady-state level. Once the steady-state level

of the control recordings had been accomplished at least for five

sweeps, cells were continuously perfused with an extracellular

solution containing the test compound. During wash-in of the

test compound, the voltage protocol indicated above was ap-

plied continuously until the effect of the test compound reached

a steady-state. Each test compound was tested on three different

cells. The tail current amplitude values were generated for each

voltage step by subtracting the mean current during the holding

1

corrected yield) and triphenylphosphine oxide (70 wt %). H

NMR (DMSO-d₆, 400 MHz): δ = -0.08 (s, 9 H), 0.83 (t, 2 H),

1.99 (m_c), 2.24 (m_c, 1 H), 2.39 (s, 3 H), 2.50 (s), 2.67 (bs, 1 H), 2.80

(s, 3 H), 2.90 (bs, 1 H), 3.02 (s, 3 H), 3.52 (t, 2 H), 5.35 (dd, 1 H),

5.54 (s, 2 H), 7.06 (s, 1 H), 7.27 (m_c, 3 H), 7.48 (m_c, 1 H);

triphenylphospine oxide: 7.59 (m_c).

(8S)-N,N,2-Trimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydro-

chromeno[7,8-d]imidazole-5-carboxamide (150). At a tempera-

ture of 0 °C, borontrifluoride etherate (290 μL, 325 mg,

2.3 mmol) was added dropwise to a solution of the protected

benzimidazole 149 (400 mg, 30 wt %, 0.25 mmol) in dichlor-

omethane (10 mL). The reaction mixture was stirred for 3 h at

room temperature, and the solvent was evaporated in the

presence of silica gel. The residue was loaded on top of a column

filled with silica gel, and the title compound was eluted with

dichloromethane/methanol = 50:1 (v/v). Evaporation of the

corresponding fractions afforded the title compound (110 mg,

quant yield, 96.1% ee). HPLC analytical method: column,

Daicel Chiralpak AD-H, 250 mm ꢀ 4.6 mm, 5 μm; eluant, n-

hexane/2-propanol = 90:10; flow rate, 1 mL/ min; detection wave-

length, 218 nm; t_R(8S) = 21.9 min/97.7 area %; t_R(8R) = 32.5

min/1.9 area %; mp 219 °C. ¹H NMR (DMSO-d₆, 200 MHz): δ

= 2.04 (m_c, 1 H), 2.26 (m_c, 1 H), 2.40 (s, 3 H), 2.53, 2.63 (s, m_c),

2.81 (s, 3 H), 2.90, 3.02 (m_c, s, 4 H), 5.43 (dd, 1 H), 6.99 (s, 1 H),

7.28 (m_c, 3 H), 7.50 (m_c, 1 H). HRMS calcd for C₂₁H₂₄N₃O₂m/z

(MH^þ), 350.1863; found, 350.1857.

5.2. Biological and Pharmacological Investigation of 3,6,7,8-

Tetrahydrochromeno[7,8-d]imidazoles. The experimental condi-

tions for the in vitro assays (competitive binding assay for

determination of the inhibitory activity against H^þ/K^þ-ATPase

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3673

€

potential at the intermediate step of -80 mV from the tail

current peak. The mean of the at least last three current

amplitudes at the steady-state in the presence of the test com-

pound was compared to that of control condition of the same

cell. The amount of current block was calculated as percentage

of control. Data from at least three individual cells were

collected.

5.4. Physical Chemistry. 5.4.1. Determination of Dissocia-

tion Constants and Distribution Coefficients. The pK_avalues

and the distribution coefficients between 1-octanol and

aqueous KCl solution of the investigated compounds were

determined by potentiometric cosolvent titrations as des-

cribed previously.⁵

5.4.2. Estimation of logD at pH 7.4 by Reversed-Phase HPLC.

The logarithmic partition coefficient logD was determined by

correlation of the HPLC retention time of an investigated

substance to a calibration curve calculated by linear regression

of retention times and the known logD values (-0.02, 1.62, 2.06,

2.82, 3.41, 4.00, 5.10) at pH 7.4 of seven substances from the

Nycomed compound library. Each substance was investigated

in a double injection HPLC experiment. The calibration sub-

stances and the sample were dissolved in DMSO to a concentra-

tion of 10.0 mM. A sample of the calibration/sample solution

(15 μL) per deep well was diluted with acetonitrile (100 μL). This

dilution was carried out directly in the deep well plate before

each first injection by the HPLC autosampler. Chromato-

graphic conditions: HPLC equipment, Hitachi LaChrom 7000

series; HPLC column, Waters X Terra C18 100 mm ꢀ 2.1 mm,

particle size 5 μM, equipped with a precolumn of 10 mm length;

diode array detection, 230-330 nm; data acquisition time, 18.9

min; column oven temperature, 37 °C; injection volume, 2.0 μL;

eluant, 10 mM ammonium acetate buffer (pH 7.4)/acetonitrile;

flow rate, 0.5 mL; gradient, 96:4 to 0:100 (0-16 min), 0:100

(16-18.2 min), 0:100 to 96:4 (18.2-18.9 min).

(4) Palmer, A. M.; Munch, G.; Brehm, C.; Zimmermann, P. J.; Buhr,

W.; Feth, M. P.; Simon, W. A. Design of novel P-CABs, IV.

5-Substituted 1H-pyrrolo[3,2-b]pyridines as inhibitors of gastric

acid secretion. Bioorg. Med. Chem. 2008, 16, 1511–1530.

(5) Palmer, A. M.; Grobbel, B.; Jecke, C.; Brehm, C.; Zimmermann, P.

J.; Buhr, W.; Feth, M. P.; Simon, W.-A.; Kromer, W. Design of

novel P-CABs, V. Synthesis and evaluation of 7H-8,9-

dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as potassium-com-

petitive acid blockers. J. Med. Chem. 2007, 50, 6240–6264.

€

(6) Palmer, A. M.; Chrismann, S.; Munch, G.; Brehm, C.; Zimmer-

mann, P. J.; Buhr, W.; Senn-Bilfinger, J.; Feth, M. P.; Simon, W. A.

Design of novel P-CABs, VI. Spiro(imidazo[1,2-a]pyrano[2,3-

c]pyridine-9-indenes) as inhibitors of gastric acid secretion. Bioorg.

Med. Chem. 2009, 17, 368–384.

(7) Schubert, M. L.; Peura, D. A. Control of gastric acid secretion in

health and disea_þse. Gastroenterology 2008, 134, 1842–1860.

(8) Bamford, M. H /K^þATPase inhibitors in the treatment of acid-

related disorders. Prog. Med. Chem. 2009, 47, 75–162.

(9) Shin, J. M.; Sachs, G. Long-lasting inhibitors of the gastric H,K-

ATPase. Expert Rev. Clin. Pharmacol. 2009, 2, 461–468.

(10) DeVault, K. R.; Talley, N. J. Insights into the future of gastric acid

suppression. Nature Rev. Gastroenterol. Hepatol. 2009, 6, 524–532.

(11) Boeckxstaens, G. Emerging drug for gastroesophageal reflux dis-

ease. Expert Opin. Emerging Drugs 2009, 1_þ4, 481–491.

(12) Munson, K. B.; Sachs, G. Inactivation of H ,K^þ-ATPase by a K^þ-

competitive photoaffinity inhibitor. Biochemistry 1988, 27, 3932–3938.

(13) Kromer, W.; Postius, S.; Riedel, R. Animal pharmacology of

reversible antagonism of the gastric acid pump, compared to

standard antisecretory principles. Pharmacology 2000, 60, 179–187.

(14) Palmer, A. M.; Chiesa, V.; Holst, H. C.; Le Paih, J.; Zanotti-

Gerosa, A.; Nettekoven, U. Synthesis of enantiopure 3,6,7,8-

tetrahydrochromeno[7,8-d]imidazoles via asymmetric ketone hy-

drogenation in the presence of RuCl₂[Xyl-P-Phos][DAIPEN].

Tetrahedron: Asymmetry 2008, 19, 2102–2110.

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(15) Palmer, A. M.; Webel, M.; Scheufler, C.; Haag, D.; Muller, B.

Large-scale asymmetric synthesis of the 3,6,7,8-tetrahydrochro-

meno[7,8-d]imidazole BYK 405879: a promising candidate for the

treatment of acid-related diseases. Org. Process Res. Dev. 2008, 12,

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(16) Palmer, A. M.; Nettekoven, U. Preparation of tricyclic imidazo-

pyridines by asymmetric ketone hydrogenation in the presence of

ruthenium phosphino-oxazoline catalyst. Tetrahedron: Asymmetry

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tricyclic imidazopyridines by asymmetric ketone hydrogenation in

the presence of RuCl₂[(S)-Xyl-P-Phos][(S)-DAIPEN]. Tetrahe-

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Acknowledgment. We are grateful to Sandra Chrismann,

Cornelia Jecke, Guido Beck, Lazlo Rusvai, Reinhard Geiger,

Jens Bruchhaus, and Oliver Meyer for chemical assistance,

Brigitte Boessenecker, Silke Wintrich, Janett Kientopp, and

Collin Hoffmann for the determination of pK_aand logD values,

Tanja Ramisch and Ivo Vidovic for the assessment of optical

purities by HPLC and capillary electrophoresis, and Klaus

€

Hagele for the acquisition of high resolution mass spectra. We

also thank Margit David and Imme Hartig-Beecken for the in

vitro evaluation of the target compounds, Astrid Hochadel and

Walter Prinz for the examination of the target compounds in the

(21) Hancox, J. C.; McPate, M. J.; El Harchi, A.; Zhang, Y. H. The

hERG potassium channel and hERG screening for drug-induced

torsades de pointes. Pharmacol. Ther. 2008, 119, 118–132.

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ade. Curr. Top. Med. Chem. 2008, 8, 1113–1127.

(23) Du, L.; Li, M.; You, Q. The interactions between hERG potassium

channel and blockers. Curr. Top. Med. Chem. 2009, 9, 330–338.

(24) Chiesa, M. V.; Palmer, A; Buhr, W.; Zimmermann, P. J.; Brehm,

C.; Simon, W.-A.; Postius, S.; Kromer, W.; Zanotti-Gerosa, A.

Process for the production of intermediates for the preparation of

tricyclic benzimidazoles. International Patent Application WO

2006/136552, 28 December 2006.

€

Ghosh Schild rat, and Uwe Brauer and Bernd Kress for the

acquisition of pH-metry curves in the fistula dog.

Supporting Information Available: Synthesis of azetidin-3-

ylmethanol, 3-methylazetidin-3-ol, and N,N-dimethylazetidine-

3-carboxamide. Assessment of purity of all target compounds

by HPLC/HRMS and/or elemental analysis. This material is

available free of charge via the Internet at http://pubs.acs.org.

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Article Doi

Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): Structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel

DOI: 10.1021/jm100040c

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Article abstract of DOI:10.1021/jm100040c

Full text of DOI:10.1021/jm100040c

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