Preparation of tetrahydroimidazo[2,1-a]isoquinolines and their use as inhibitors of gastric acid secretion

Available online at www.sciencedirect.com

Bioorganic & Medicinal Chemistry 15 (2007) 7647–7660

Preparation of tetrahydroimidazo[2,1-a]isoquinolines and their

use as inhibitors of gastric acid secretion^q

Andreas Marc Palmer,^*Burkhard Grobbel, Christof Brehm, Peter Jan Zimmermann,

Wilm Buhr, Martin Philipp Feth, Hans Christof Holst and Wolfgang Alexander Simon

NYCOMED GmbH, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany

Received 26 June 2007; revised 8 August 2007; accepted 31 August 2007

Available online 5 September 2007

Abstract—A series of novel tetrahydroimidazo[2,1-a]isoquinolines was prepared based on a hetero Diels–Alder reaction between an

enamine and 1,2,4-triazine as key step. A structure–activity relationship was established focussing on the inﬂuence of the substitu-

tion pattern in position 3 and 6 of the heterocycle on antisecretory activity, lipophilicity, and pK_avalue. Potent inhibitors of the

gastric acid pump were identiﬁed.

1. Introduction

H⁺/K⁺-ATPase and have long been available as thera-

peutics. A new class of compounds designated as acid

pump antagonists (APAs) or as potassium competitive

acid blockers (P-CABs) bind reversibly to the H⁺/K⁺-

ATPase. Although PPIs are considered as the gold stan-

dard for the treatment of acid-related diseases, P-CABs

might oﬀer some therapeutic advantages such as better

symptom control and faster healing.^5,6

Gastroesophageal reﬂux disease (GERD), the backward

ﬂow of the stomach’s contents into the esophagus, is a

digestive condition that aﬀects 20% of the American

population and is often manifested by heartburn, which

is characterized by burning pain that radiates through

chest, neck, and throat.^1,2Peptic ulcer disease, estimated

to aﬀect 14.5 million people in the United States, is a

chronic inﬂammation of the stomach and duodenum

and is responsible for a large economic burden. The for-

mation of peptic ulcers is favored by two factors: the

hypersecretion of acid and a weakened resistance of

the protective mucous coating of the stomach and duo-

denum.^3,4The inhibition of acid secretion and the neu-

tralization of formed acid constitute eﬀective

In the past two decades, one important approach for the

identiﬁcation of potent P-CABs relied on the structural

class of substituted imidazo[1,2-a]pyridines. The inhibi-

tor SCH 28080 (1) represents the clinical prototype of

this series. SCH 28080 (1) inhibits the gastric proton

pump enzyme (H⁺/K⁺-ATPase) by a kinetically compet-

itive and reversible inhibition mechanism with respect to

the potassium ion and shows excellent antisecretory and

cytoprotective properties.^7–9However, the clinical devel-

opment of SCH 28080 (1) was stopped due to extensive

metabolism and associated liver toxicity⁸(Fig. 1).

approaches for the treatment of both diseases.^1,3

A

whole series of compounds, which inhibit gastric acid

secretion by blockade of the gastric proton pump

enzyme (H⁺/K⁺-ATPase), are known. Compounds des-

ignated as proton pump inhibitors (PPIs), for example,

omeprazole, esomeprazole, lansoprazole, pantoprazole,

rabeprazole, or tenatoprazole bind irreversibly to the

One approach to synthesize advanced chemical ana-

logues of SCH 28080 was based on molecular modeling

results, which suggested that in the gas phase, SCH

28080 could adopt various ‘folded’ conformations close

to the global minimum of energy.^9,10On the other hand,

single-crystal X-ray analysis revealed that solid SCH

28080 existed in an ‘extended’ conformation.^7,10The

synthesis of simple analogues, which imitated these

conformations, demonstrated that an ‘extended’

relationship between the phenyl group and the heterocy-

Keywords: Hetero Diels–Alder reaction; Tetrahydroimidazo[2,1-a]iso-

quinolines; Antisecretory activity; Gastric acid pump; H⁺/K⁺-ATPase.

q

Design of novel P-CABs, II.—Part I: Zimmermann, P. J.; Buhr, W.;

Brehm, C.; Palmer, A. M.; Feth, M. P.; Senn-Bilﬁnger, J.; Simon,

W.-A. Bioorg. Med. Chem. Lett. 2007, doi:10.1016/j.bmcl.2007.08.003.

*

Corresponding author. Tel.: +49 7531 84 4783; fax: +49 7531 849

2087; e-mail: andreas.palmer@nycomed.com

doi:10.1016/j.bmc.2007.08.065

7648

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

yl)pyrrolidine (5) with 1,2,4-triazine (13).^11,12,14This

CN

transformation is believed to proceed via the intermedi-

ates 6 and 7, which are formed by [4+2] cycloaddition

and extrusion of nitrogen, respectively (Scheme 1).¹⁴

The reaction sequence is completed by the elimination

of pyrrolidine aﬀording 7-phenyl-5,6,7,8-tetrahydroiso-

quinoline (8). Enamine 5 was synthesized by a titanium

tetrachloride mediated condensation of 4-phenylcyclo-

hexanone (4) and pyrrolidine.¹⁵1,2,4-Triazine (13) was

prepared in four steps (Scheme 1) beginning with the

treatment of commercially available ethyl amino(thi-

oxo)acetate (9) with hydrazine to aﬀord ethyl

amino(hydrazono)acetate (10).^16,17Ethyl 1,2,4-triazine-

3-carboxylate (11) was then secured by condensation

of 10 with freshly prepared glyoxal.¹⁸Finally, saponiﬁ-

cation of the ester moiety and decarboxylation of the

intermediate carboxylic acid 12 aﬀorded 1,2,4-triazine

(13) in 26% overall yield. 7-Phenyl-5,6,7,8-tetrahydro-

isoquinoline (8) was obtained in 84% yield by reﬂuxing

a solution of enamine 5 and 1,2,4-triazine (13) in chloro-

form for 18 h. This transformation was also feasible in

larger scale using up to 20 g of starting material.

N

7

N

Ph

O

Ph

SCH 28080 (1)

(" folded")

("extended")

R³

CN

R⁶

N

O

Ph

2

3

Figure 1.

clic nucleus was required for eﬀective binding to H⁺/K⁺-

ATPase.⁹Subsequently, the 7H-8,9-dihydropyrano[2,3-

c]imidazo[1,2-a]pyridine 2 was synthesized in which the

pyrano ring was considered to enforce this requisite ‘ex-

tended’ relationship and to mimic a 7-methyl substituent

which would be eﬀective in overcoming the toxic proper-

ties of 1 while retaining its desirable antisecretory

eﬀects.^9,11

7-Phenyl-5,6,7,8-tetrahydroisoquinolin-1-amine (14) was

prepared by Chichibabin reaction involving the heating

of 7-phenyl-5,6,7,8-tetrahydroisoquinoline (8) with so-

dium amide (Scheme 2) in a high boiling solvent, for

example, degassed N,N-dimethylaniline or tetralin

(220 ꢁC, 18 h), to provide 14 in 41–48% yield.¹⁹We also

examined the possibility to perform the Chichibabin

reaction under microwave-assisted conditions. However,

at a temperature of 210 ꢁC, a mixture of 14 with its

aromatic analogue (7-phenylisoquinolin-1-amine) was

In the course of our eﬀorts to identify novel P-CABs, we

were interested in the synthesis of tetrahydroimi-

dazo[2,1-a]isoquinolines of the general formula 3, which

represent carbocyclic analogues of the 7H-8,9-dihydro-

pyrano[2,3-c]imidazo[1,2-a]pyridine 2.¹²As the oxida-

tive decyanation of 1 was identiﬁed as the major

metabolic pathway of SCH 28080 (1), one important

goal was to identify potent inhibitors that are devoid

of the 3-cyanomethyl moiety.⁸

isolated. Whereas the amination of

8 proceeded

smoothly at a temperature of 180 ꢁC (59% yield), the

reaction time (12 h) could not be signiﬁcantly reduced

with respect to the thermal variant. The activating and

para-directing properties of the newly installed amino

group were used to prepare 4-bromo-7-phenyl-5,6,7,8-

tetrahydroisoquinolin-1-amine (15) by electrophilic

substitution of 14 with N-bromosuccinimide. The con-

struction of the tetrahydroimidazo[2,1-a]isoquinoline

framework was completed by transformation of the

intermediates 14 and 15 either with chloroacetone or

3-bromobutanone (Scheme 2) aﬀording the products

16–19 in 46–81% yield.²⁰

A second goal was the modulation of the pK_avalue by

introduction of diﬀerent substituents R⁶. The pK_avalue

of a potassium competitive acid blocker is an important

parameter for two reasons: ﬁrst, it determines the con-

centration of the protonated species, which is the active

form for inhibiting H⁺/K⁺-ATPase in the parietal

cell.^6,13Second, the parietal cell is distinguished from

other compartments by its low pH value of approxi-

mately 3. Hence, P-CABs with low pK_avalues are accu-

mulated in a selective manner and possible interactions

with enzymes that are expressed in other cells are pre-

vented, which should translate in an improved safety

proﬁle.

In order to obtain target compounds 3, which are substi-

tuted by a carboxamide residue, we examined the

alkoxycarbonylation of 6-bromo-tetrahydroimidazo

[2,1-a]isoquinoline 19 (Scheme 3).²¹Heating a mixture

of bromide 19, palladium acetate (10 mol %), triphenyl-

phosphine, triethylamine, and ethanol under a pressure

of 6 bar carbon monoxide for 18 h at 115 ꢁC aﬀorded

ethyl carboxylate 20 in 90% yield. After saponiﬁcation

of the ester function, carboxamides 22–28 were obtained

in good yields by the reaction of carboxylic acid 21 with

the respective amine and TBTU as coupling agent.²²

Ethyl carboxylate 20 also served as a starting material

for the synthesis of the 6-methoxymethyl derivative 31:

after reducing the ester group with lithium aluminium

hydride, the newly formed hydroxy group was converted

with thionyl chloride to furnish chloride 30. Finally,

2. Results and discussion

2.1. Synthesis of tetrahydroimidazo[2,1-a]isoquinolines

The synthesis of the target compounds was based on

7-phenyl-5,6,7,8-tetrahydroisoquinoline (8) as key

intermediate, which in turn was obtained by hetero

Diels–Alder reaction of 1-(4-phenylcyclohex-1-en-1-

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7649

N

O

N

(i)

(ii)

N

Ph

4

5

6

7

8

O

H₂N

N

(iv)

(iii)

(v)

(vi)

OEt

OH

S

N

H₂N

N

9

10

11

12

13

Scheme 1. Reagents and conditions: (i) pyrrolidine, TiCl₄, rt, 3 h, 86%; (ii) 13, CHCl₃, 60 ꢁC, 18 h, 84%; (iii) N₂H₄, THF, EtOH, rt, 3 h, 86%; (iv)

glyoxal, HOAc, THF, ꢀ75 ꢁC, 0.25 h, then NEt₃, rt, 3 h, 51%; (v) KOH, EtOH, rt, 0.25 h, 89%; 1 N HCl, 77%; (vi) D, 125 ꢁC, 1.25 h, distillation,

88%.

Br

2.2. Inhibitory activity and physicochemical properties of

tetrahydroimidazo[2,1-a]isoquinolines

N

(ii)

(i)

NH₂

The inhibitory and cellular activity of the tetrahydroim-

idazo[2,1-a]isoquinolines 16, 17, 22–28, 31–33, and 35

was evaluated in a competitive binding assay against

H⁺/K⁺-ATPase from hog gastric mucosa and by deter-

mination of acid formation in gastric glands. Addition-

ally, the lipophilicity and pK_avalues of selected target

compounds were determined. The data reported for

7H-8,9-dihydrohydropyrano[2,3-c]imidazo[1,2-a]pyridine

2 was obtained from the literature.¹³The results are

summarized in Table 1.

Ph

15

8

14

(iii) or (iv)

Br

R

N

Although the inhibitory activity of 7H-8,9-dihydropyr-

ano[2,3-c]imidazo[1,2-a]pyridine 2 remained unequaled,

it was demonstrated that the problematic cyanomethyl

group could be replaced by a methyl residue without a

signiﬁcant loss of aﬃnity toward the gastric proton

pump enzyme. On the other hand, this replacement

caused an unfavorable alteration of the dissociation

constant (17 vs 2). A substantial decrease of both the

pK_avalue and the lipophilicity with respect to com-

pound 17 can be accomplished by introduction of a car-

boxamide residue. Whereas the carboxamide function in

general exerts a beneﬁcial inﬂuence on the pK_avalue and

the lipophilicity of the target compounds, the strength of

inhibition clearly depends on the nature of the amide

residue. The IC₅₀values determined for carboxamides

22–25 and 27 are comparable with the IC₅₀value of

the 6-unsubstituted derivative 17. Carboxamides 26

(methoxyethyl) and 28 (morpholin-4-yl) represent exam-

ples for weak inhibitors. The presence of a methoxy-

methyl moiety in 6-position also resulted in strong

enzyme inhibition (compound 31). However, the pri-

mary goal to improve the physicochemical properties

with respect to inhibitor 2 was not accomplished with

this substituent.

Ph

R=H: 18

R=H: 16

R=Me: 17

R=Me: 19

Scheme 2. Reagents and conditions: (i) variant 1: NaNH₂, tetralin,

argon-ﬁlled autoclave, 220 ꢁC, 18 h, 48%; variant 2: NaNH₂, N,N-

dimethylaniline, argon-ﬁlled autoclave, 220 ꢁC, 18 h, 41%; variant 3:

NaNH₂, N,N-dimethylaniline, argon-ﬁlled microwave vial, 180 ꢁC

(MW), 12 h, 59%; (ii) NBS, CH₃CN, rt, 0.75 h, 88%; (iii) chloroac-

etone, THF, 2.5–4.5 d, 16: 46%, 18: 81%; (iv) 3-bromobutanone, THF,

70 ꢁC, 1–7 d, 17: 75%, 19: 66%.

methyl ether 31 was obtained by nucleophilic substitu-

tion of 30 with sodium methylate.

Carboxamide 32 was synthesized in an analogous

manner as described for carboxylic ester 19: amino-

carbonylation of the 6-bromo intermediate 18 was

accomplished in the presence of palladium acetate

and triphenylphosphine using dimethylamine in

tetrahydrofuran instead of ethanol.²¹Tetrahydroimi-

dazo[2,1-a]isoquinoline 32 was then functionalized in

the 3-position either by bromination with N-bromosuc-

cinimide or by Vilsmeier formylation to furnish com-

pounds 33 and 34. Reduction of aldehyde 34 with

sodium borohydride aﬀorded the corresponding alco-

hol 35 (Scheme 4).

As expected, the nature of the 3-substituent also exerts a

strong inﬂuence on the pK_avalue. The comparison of

the analogues 24 (3-methyl), 32 (3-unsubstituted), 33

(3-bromo), and 35 (3-hydroxymethyl) reveals that the

nature of the 3-substituent also plays a crucial role for

7650

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

O

Br

R²R¹N

N

EtO

N

HO

N

(i)

(ii)

(iii)

19

20

21

22: NR¹R²= NH₂

(iv)

(v)

23: NR¹R²= NH(CH₃)

24: NR¹R²= N(CH₃)₂

25: NR¹R²= NH[(CH₂)₂OH]

26: NR¹R²= NH[(CH₂)₂OCH₃]

HO

N

Cl

N

O

N

27: NR¹R²= pyrrolidine

28: NR¹R²= morpholine

N

(vi)

29

30

31

Scheme 3. Reagents and conditions: (i) Pd(OAc)₂, PPh₃, Et₃N, EtOH, 6 bar CO, 115 ꢁC, 18 h, 90%; (ii) KOH, MeOH/H₂O, 60 ꢁC, 3 h, 93%; (iii)

TBTU, CH₂Cl₂, 40 ꢁC, 1 h, 22: NH_3(g), rt, 1 h, 65%, 23: MeNH₂(2 M solution in THF), rt, 1 h, 56%, 24: HNMe₂(2 M solution in THF), rt, 3 h, 72%,

25: 2-aminoethanol, rt, 2 h, 57%, 26: 2-methoxyethylamine, rt, 2 h, 74%, 27: pyrrolidine, rt, 1 h, 86%, 28: morpholine, rt, 1 h, 81%; (iv) LiAlH₄, THF,

rt, 1 h, 44%; (v) SOCl₂, CH₂Cl₂, rt, 1 h, 87%; (vi) NaOMe, MeOH, 60 ꢁC, 1.5 h, 87%.

the strength of enzyme inhibition. The fact that a 3-

methyl group is required for potent enzyme inhibition

is also evident from the comparison of the 6-unsubstitut-

ed tetrahydroimidazo[2,1-a]isoquinolines 16 and 17

where a diﬀerence in activity of more than factor 10

was observed. In all cases, potent enzyme inhibition

translates into a good reduction of acid secretion in gas-

tric glands.

tography 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 vapour or by irradiation with ultraviolet light

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

laries on a Buchi B-540 melting point apparatus and are

¨

uncorrected. ¹H NMR spectra were recorded with a

Bruker DRX 200 FT-NMR spectrometer at a frequency

of 200.1 MHz, a Bruker AV 400 FT-NMR spectrometer

at a frequency of 400.1 MHz, or a Bruker AV 600 FT-

NMR spectrometer at a frequency of 600.1 MHz. ¹³C

NMR spectra were acquired with a Bruker AV 400

FT-NMR spectrometer at a frequency of 100.7 MHz

or a Bruker AV 600 FT-NMR spectrometer at a fre-

quency of 150.9 MHz. CDCl₃or DMSO-d₆was used

as solvent. The chemical shifts were reported as parts

per million (d ppm) with tetramethylsilane (TMS) as

an internal standard. High resolution mass spectra were

obtained on a Bruker Daltonics MicroTOF Focus

instrument using electrospray ionization (ESI positive).

Elemental analysis was performed on a Carlo Erba

1106 C, H, N analyzer.

3. Conclusion

In summary, we report a general route for the prepara-

tion of 6-substituted tetrahydroimidazo[2,1-a]isoquino-

lines. The metabolically labile cyanomethyl group that

constitutes a key structural element in SCH 28080 was

replaced by a methyl residue without signiﬁcant loss of

aﬃnity toward the gastric proton pump enzyme. The

incorporation of an amide moiety resulted in derivatives

with signiﬁcantly reduced pK_aand logD values.

Although the carbocyclic analogue of reference com-

pound 2 was not prepared, it seems that the ring oxygen

atom can be substituted with a carbon atom without

considerable loss of aﬃnity toward H⁺/K⁺-ATPase.

4.1.2. 1-(4-Phenyl-cyclohex-1-enyl)-pyrrolidine (5). In a

ﬂame-dried ﬂask ﬁlled with argon, 4-phenylcyclohexa-

none (4) (12.5 g, 72 mmol) was suspended in dry hexane

(250 ml) and a solution of pyrrolidine (25.0 g, 350 mmol)

in hexane (30 ml) was added. The clear solution was

cooled to 0 ꢁC and a solution of titanium tetrachloride

(6.8 g, 36 mmol) in hexane (50 ml) was added dropwise

over a period of 1 h during which a green-white precipi-

tate was formed. The reaction mixture was allowed to

come to room temperature and stirring was continued

for 3 h. The precipitate was removed by ﬁltration and

was washed with hexane (2· 20 ml). The ﬁltrates were

concentrated under reduced pressure. An oily residue

(13.5 g) was isolated which was characterized by ¹H

4. Experimental

4.1. Chemistry

4.1.1. General. All chemicals were purchased from the

major chemical suppliers as highest purity grade and

used without any further puriﬁcation. 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 dichloro-

methane/methanol as solvent system. Column chroma-

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7651

column chromatography [500 g of silica gel, eluant:

ethyl acetate/petrol ether = 1:1 (v/v)]. A brownish oil

(44.0 g, 84% yield) was isolated which was characterized

as the pure title compound: ¹H NMR (200 MHz,

CDCl₃): d = 1.92 (m_c, 1H), 2.15 (m_c, 1H), 2.93 (m_c,

5H), 7.02 (d, 1H), 7.28 (m_c), 8.31 (d, 1H), 8.33 (s, 1H);

HRMS (ESI) m/z C₁₅H₁₆N [M+H]⁺Calcd: 210.1277.

Found: 210.1269.

Br

N

18

4.1.4. Ethyl amino(hydrazono)acetate (10). In a ﬂame-

dried ﬂask ﬁlled with argon, amino(thioxo)acetate (9)

(13.3 g, 0.1 mol) was dissolved in ethanol (300 ml),

which had been degassed with argon. The red solution

was stirred at room temperature and a 1 M solution of

hydrazine in THF (100 ml, 0.1 mol) was added over a

period of 30 min during which hydrogen sulﬁde was lib-

erated. The reaction was further stirred for 2.5 h at

room temperature. After concentration of the yellow

solution under reduced pressure, a yellow-red residue

(22 g) was obtained which was recrystallized from petrol

ether/dichloromethane [420 ml, 3:1 (v/v)]. The solution

was ﬁltered and the red, oily residue was discarded.

From the ﬁltrate a yellowish solid separated, which

was collected by ﬁltration and washed with petrol ether.

Ethyl amino(hydrazono)acetate (10) was obtained in

54% yield (7.1 g): mp 92–94 ꢁC; ¹H NMR (CDCl₃,

200 MHz): d = 1.38 (t, 3H), 4.35 (q, 2H), 4.52 (br s, 4H).

(i)

O

Br

N

(ii)

32

(iii)

33

O

H

O

OH

N

4.1.5. Ethyl 1,2,4-triazine-3-carboxylate (11). Mono-

meric glyoxal was prepared by heating the trimer

(45 g) to 160 ꢁC in the presence of phosphorus pentox-

ide (110 g).¹⁸The glyoxal formed was condensed into a

trap cooled with liquid nitrogen and dissolved in dry

THF. The monomer obtained (14 g) was pure by

means of ¹H NMR spectroscopy: ¹H NMR (CDCl₃,

200 MHz): d = 9.30 (s, CHO). A solution of mono-

meric glyoxal (5 g) in THF (50 ml) was transferred into

a ﬂame-dried ﬂask ﬁlled with argon and cooled to

ꢀ78 ꢁC. A pre-cooled solution (ꢀ78 ꢁC) of hydrazono

ester 10 (11.0 g, 84 mmol) and glacial acetic acid

(13 ml) in absolute ethanol (260 ml) was added over a

period of 2 min. The red-yellow reaction mixture was

stirred for 15 min at ꢀ75 ꢁC. After addition of triethyl-

amine (13 ml), the cooling bath was removed and the

solution was stirred for 3 h at room temperature. It

was then poured onto a mixture of saturated sodium

bicarbonate solution (100 ml), ice water (200 ml), and

dichloromethane (300 ml) and stirred for several more

minutes. The phases were separated and the aqueous

phase was extracted with dichloromethane (3· 100 ml).

The combined organic phases were washed with water

(3· 100 ml), dried over sodium sulfate, and concentrated

under reduced pressure. The remaining yellow solid

(20 g) was puriﬁed by column chromatography (500 g

of silica gel, solvent: dichloromethane). Ethyl 1,2,4-tri-

azine-3-carboxylate (11) was obtained as a yellow-brown

oil (6.6 g, 51%) that solidiﬁed within a few hours: mp

N

(iv)

N

34

35

Scheme 4. Reagents and conditions: (i) Pd(OAc)₂, PPh₃, HNMe₂,

NEt₃, THF, 6 bar CO, 120 ꢁC, 19 h, 69%; (ii) NBS, CH₂Cl₂, ꢀ75 ꢁC,

1 h, 89%; (iii) POCl₃, DMF, rt, 1.5 h, then addition of 32, DMF, 60 ꢁC,

3 h, 78%; (iv) NaBH₄, MeOH, rt, 0.5 h, 63%.

NMR-spectroscopy. The sample contained 81 wt% of 1-

(4-phenyl-cyclohex-1-enyl)-pyrrolidine (10.9 g, 68%

yield), 15 wt% of 4-phenylcyclohexanone, and 4 wt% of

pyrrolidine: H NMR (200 MHz, DMSO-d₆): d = 1.78,

2.25, 2.95 (3 m_c), 4.18 (m_c, 1H), 7.25 (m_c).

1

4.1.3. 7-Phenyl-5,6,7,8-tetrahydro-isoquinoline (8). In a

ﬂame-dried ﬂask ﬁlled with argon, 1,2,4-triazine (13)

(20.0 g, 0.25 mol) was dissolved in dry chloroform

(200 ml). A solution of 1-(4-phenyl-cyclohex-1-enyl)-

pyrrolidine (5) (92.0 g, 75 wt%, 0.30 mol) in chloroform

(180 ml) was added slowly. The red solution was heated

to 60 ꢁC for 18 h. The reaction mixture was cooled to

0 ꢁC and poured onto saturated ammonium chloride

solution (300 ml). Stirring was continued for several

minutes and the phases were separated. The aqueous

phase was extracted with chloroform (2· 50 ml). The

combined organic phases were washed with saturated

ammonium chloride solution (2· 80 ml) and water (2·

80 ml), dried over sodium sulfate and evaporated to dry-

ness. The residue (130 g of a brown oil) was puriﬁed by

1

70 ꢁC; H NMR (CDCl₃, 200 MHz): d = 1.51 (t, 3H),

4.62 (q, 2H), 8.85 (d, 1H), 9.44 (d, 1H).

4.1.6. 1,2,4-Triazine-3-carboxylic acid (12). Ethyl car-

boxylate 11 (5.8 g, 38 mmol) was dissolved in dry etha-

nol (80 ml). A ﬁltered solution of potassium hydroxide

7652

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

Table 1. Inhibitory activity and physicochemical properties of compounds 2, 16, 17, 22–28, 31–33, 35

R³

R⁶

N

Ph

3

Compound

2 (lit.¹³

R³

R⁶

H⁺/K⁺-ATPase ꢀlogIC₅₀

7.0

Gastric glands ꢀlogIC₅₀

7.2

pK_a

logD (pH 7.4)

)

6.0

16

H

5.1

6.6

5.9

5.1

6.1

5.7

7.63

8.05

7.26

3.81

3.90

3.21

17

CH₃

O

22

H₂N

O

23

24

25

26

27

28

31

32

33

35

CH₃

H

6.2

6.0

5.9

4.9

5.9

5

6.0

6.4

5

N

H

O

7.16

7.22

7.20

7.05

7.79

6.67

5.11

6.32

2.90

2.81

3.31

3.37

2.76

3.93

2.77

3.80

2.23

N

O

HO

N

H

O

MeO

5.9

6.5

5.2

5.7

5.1

5.0

N

H

O

N

O

N

O

6.3

4.8

4.9

5.5

O

N

O

Br

O

CH₂OH

(2.3 g, 41 mmol) in dry ethanol (60 ml) was then added

over a period of 40 min at room temperature. The result-

ing light-brown suspension was stirred for additional

15 min at room temperature. The precipitate was

isolated by ﬁltration, washed with ethanol (10 ml), and

dried in vacuo. The potassium salt of 12 was obtained

1

in 89% yield (5.5 g): H NMR (DMSO-d₆, 200 MHz):

d = 8.66 (d, 1H), 9.19 (d, 1H). 1,2,4-Triazine-3-carbox-

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7653

ylic acid (12) was obtained by dissolving the potassium

salt of 12 (5.4 g, 33 mmol) in 34 ml of 1 N hydrochloric

acid. The yellow-brown solution was freeze-dried over-

night. The obtained mixture of potassium chloride and

1,2,4-triazine carboxylic acid was treated with water

(7 ml). The resulting suspension was stirred for 40 min

and was then ﬁltered. The residue was washed with

water (3 ml) and dried under reduced pressure (desiccat-

ing agent: phosphorus pentoxide). 1,2,4-Triazine-3-car-

removed by column chromatography (700 g of silica gel,

eluant: dichloromethane). After exchange of the eluant

[diethyl ether/triethylamine = 20:1 (v/v)], 2.6 g of the ti-

tle compound 14 (48% yield, yellow-brown solid) and

0.85 g of its regioisomer (7-phenyl-5,6,7,8-tetrahydro-

isoquinolin-3-yl-amine, 16% yield, brown solid contain-

1

ing impurities) were eluted: mp 124–125 ꢁC; H NMR

(200 MHz, CDCl₃): d = 1.91 (m_c, 1H), 2.12 (m_c, 1H),

2.45 (m_c, 1H), 2.75 (m_c, 3H), 3.02 (m_c, 1H), 4.32 (br s,

2H), 6.50 (d, 1H), 7.31 (m_c), 7.85 (d, 1H). Anal. Calcd

for C₁₅H₁₆N₂: C, 80.32; H, 7.19; N, 12.49. Found: C,

80.26; H, 7.19; N, 12.32.

1

boxylic acid (12) was obtained in 91% yield (3.2 g): H

NMR (DMSO-d₆, 200 MHz): d = 9.03 (d, 1H), 9.60 (d,

1H, 6-H). If the sample contained traces of water, a sec-

1

ond set of signals was visible in the H NMR spectrum.

4.1.9. 4-Bromo-7-phenyl-5,6,7,8-tetrahydro-isoquinolin-1-

yl-amine (15). In a ﬂask ﬁlled with argon, 7-phenyl-

5,6,7,8-tetrahydro-isoquinolin-1-yl-amine (14) (4.20 g,

18.7 mmol) was dissolved in dry acetonitrile (60 ml).

N-Bromosuccinimide (3.50 g, 19.7 mmol) was added in

small portions over a period of 20 min. The slightly

red-colored reaction mixture was stirred for 30 min at

room temperature. The obtained suspension was poured

onto a mixture of ice (80 g), saturated ammonium chlo-

ride solution (50 ml), and ethyl acetate (120 ml). The

phases were separated and the aqueous phase was ex-

tracted with ethyl acetate (50 ml). The combined organic

phases were washed with water (80 ml), dried over so-

dium sulfate, and concentrated under reduced pressure.

Thus, 5.50 g of the title compound 15 (97% yield) was

isolated. Traces of impurities (succinimide) were visible

4.1.7. 1,2,4-Triazine (13). A ﬂask containing the dry car-

boxylic acid 12 (7.4 g, 59 mmol) was placed in a pre-

heated oil bath (T = 120 ꢁC). 1,2,4-Triazine (13) formed

by decarboxylation of 12 was collected in a recipient

cooled to ꢀ75 ꢁC (acetone/dry ice bath). The destillation

of 13 was facilitated by application of reduced pressure

(p = 30 mbar). Within 40 min, a total amount of 2.0 g

(42% yield) of 1,2,4-triazine (13) was collected in the re-

cipient. Rinsing of the destillation apparatus with

dichloromethane yielded further 0.58 g (12% yield) of

13: ¹H NMR (CDCl₃, 200 MHz): d = 8.67 (d, 1H),

9.32 (t, 1H), 9.75 (d, 1H).

4.1.8. 7-Phenyl-5,6,7,8-tetrahydro-isoquinolin-1-yl-amine

(14). (a) Microwave synthesis: In an argon-ﬁlled micro-

wave reaction vessel, 7-phenyl-5,6,7,8-tetrahydro-iso-

quinoline (8) (0.25 g, 1.2 mmol) was dissolved in

dimethylaniline (6.3 ml). Under an argon atmosphere,

sodium amide pellets (0.16 g, 4.1 mmol) were crushed

and added to the reaction mixture. The vessel was closed

and heated to 180 ꢁC in a microwave oven (Emry’s opti-

miser, Personal Chemistry, power input: 20–25 W, pres-

sure: 7.1–8.5 bar) for 12 h. The reaction mixture was

poured onto a cold mixture of saturated ammonium

chloride solution (30 ml) and ethyl acetate (30 ml). Stir-

ring was continued for several minutes. The phases were

separated and the aqueous phase was extracted with

ethyl acetate (2· 15 ml). The combined organic phases

were washed with saturated ammonium chloride solu-

tion (2· 15 ml) and water (2· 20 ml), dried over sodium

sulfate, and evaporated to dryness. The obtained brown

liquid was puriﬁed by column chromatography (15 g of

silica gel 15–25 lm, eluant: dichloromethane) to give

160 mg (59% yield) of the title compound 14. (b) Ther-

mal synthesis: In a steel-autoclave ﬁlled with argon,

7-phenyl-5,6,7,8-tetrahydro-isoquinoline (8) (5.00 g,

23.9 mmol) was dissolved in degassed tetralin (50 ml).

Crushed sodium amide pellets (2.8 g, 72 mmol) were

added and the resulting suspension was heated for

18 h to 220 ꢁC. The dark-brown reaction mixture was

cooled to room temperature and poured onto a mixture

of saturated ammonium chloride solution (50 ml) and

dichloromethane (80 ml). The phases were separated

and the aqueous phase was extracted with dichloro-

methane (2· 20 ml). The combined organic phases were

washed with saturated ammonium chloride solution

(50 ml) and water (2· 30 ml), dried over sodium sulfate,

and concentrated under reduced pressure. The obtained

dark-brown residue (60 g) contained tetralin, which was

1

in the H NMR spectrum of the brown solid: mp 122–

125 ꢁC; ¹H NMR (200 MHz, CDCl₃): d = 1.92 (m_c,

1H), 2.19 (m_c, 1H), 2.47 (m_c, 1H), 2.71 (m_c, overlay with

succinimide: 2.75), 2.98 (m_c, 2H), 4.50 (br s, 2H), 7.33

(m_c), 8.02 (s, 1H); HRMS (ESI) m/z C₁₅H₁₆BrN₂

[M+H]⁺Calcd: 303.0491. Found: 303.0490.

4.1.10. 2-Methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo

[2,1-a]isoquinoline (16). 7-Phenyl-5,6,7,8-tetrahydro-iso-

quinolin-1-yl-amine (14) (500 mg, 2.23 mmol) was dis-

solved in dry THF (10 ml). Chloroacetone (0.37 g,

0.32 ml, 4.0 mmol) was added and the solution was

heated to reﬂux. After a reaction time of 2.5 d, the red

suspension was cooled to room temperature. Dichloro-

methane (20 ml) and water (10 ml) were added and the

reaction mixture was neutralized by addition of 25%

aqueous ammonia solution. The phases were separated

and the aqueous phase was extracted with dichloro-

methane (2· 5 ml). The combined organic phases were

washed with water (10 ml), dried over sodium sulfate,

and concentrated under reduced pressure. The crude

product (600 mg) was puriﬁed by column chromatogra-

phy (25 g of silica gel, solvent: diethyl ether) and wash-

ing with diethyl ether (5 ml). Tetrahydro-imidazo[2,1-

a]isoquinoline 16 was isolated in 46% yield (270 mg of

a

colorless solid): mp 113–115 ꢁC; ¹H NMR

(400 MHz, DMSO-d₆): d = 1.90 (m_c, 1H, 8-H_a), 2.05

(m_c, 1H, 8-H_b), 2.29 (s, 3H, 2-CH₃), 2.81 (m_c, 3H,

7-H, 10-H_a), 2.99 (m_c, 1H, 9-H), 3.25 (m_c, 1H, 10-H_b),

6.57 (d, J = 6.9 Hz, 1H, 6-H), 7.24 (m_c, 1H, Ph), 7.35

(m_c, 4H, Ph), 7.55 (s, 1H, 3-H), 8.19 (d, J = 6.9 Hz,

1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-d₆): d = 14.2

(2-CH₃), 28.3 (C-7), 29.3 (C-8), 31.4 (C-10), 38.7 (C-9),

109.6 (C-3), 113.1 (C-6), 122.6 (C-10a), 123.1 (C-5),

7654

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

126.1 (Ph), 126.7 (Ph), 128.3 (Ph), 130.8 (C-6a), 141.1

(C-2), 144.0 (C-10b), 146.0 (Ph). Anal. Calcd for

C₁₈H₁₈N₂: C, 82.41; H, 6.92; N, 10.68. Found: C,

82.33; H, 6.89; N, 10.71.

(2-CH₃), 28.5 (C-8), 29.8 (C-7), 31.2 (C-10), 37.3 (C-9),

111.8 (C-3), 126.1 (C-5), 126.5 (Ph), 126.8 (Ph), 128.5

(Ph), quarternary carbon atoms: 114.1, 121.7, 133.7,

137.8, 139.6, 144.5; HRMS (ESI) m/z C₁₈H₁₈BrN₂

[M+H]⁺Calcd: 341.0648. Found: 341.0628.

4.1.11. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-imi-

dazo[2,1-a]isoquinoline (17). 7-Phenyl-5,6,7,8-tetrahy-

dro-isoquinolin-1-yl-amine (14) (600 mg, 2.60 mmol)

was dissolved in dry THF (8 ml). 3-Bromobutanone

(0.72 g, 0.50 ml, 4.8 mmol) was added and the solution

was heated to reﬂux. After a reaction time of 24 h, the

suspension was cooled to 0 ꢁC and stirred at this temper-

ature for 45 min. The precipitate formed was isolated by

ﬁltration, washed with THF (5 ml) and diethyl ether

(5 ml), and dried in vacuo. The hydrobromide salt of

17 (860 mg, 93%) showed a mp of 223–225 ꢁC (de-

comp.). A solution of the hydrobromide salt of 17

(800 mg, 2.24 mmol) in dichloromethane (5 ml) and

water (5 ml) was treated with an aqueous ammonia solu-

tion (25%) until a pH value of 8 was obtained. The

phases were separated and the aqueous phase was ex-

tracted with dichloromethane (2· 3 ml). The combined

organic phases were washed with water (5 ml), dried

over sodium sulfate, and concentrated under reduced

pressure. The crude product was puriﬁed by crystalliza-

tion from diethyl ether (5 ml). Tetrahydro-imidazo[2,1-

a]isoquinoline 17 was obtained in 75% overall yield

(500 mg of a colorless solid): mp 160–161 ꢁC; ¹H

NMR (400 MHz, DMSO-d₆): d = 1.90 (m_c, 1H, 8-H_a),

2.06 (m_c, 1H, 8-H_b), 2.26 (s, 3H, 2-CH₃), 2.34 (s, 3H,

3-CH₃), 2.82 (m_c, 3H, 7-H, 10-H_a), 2.99 (m_c, 1H, 9-H),

3.25 (m_c, 1H, 10-H_b), 6.62 (d, J = 6.9 Hz, 1H, 6-H),

7.24 (m_c, 1H, Ph), 7.34 (m_c, 4H, Ph), 7.91 (d,

J = 6.9 Hz, 1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-

d₆): d = 7.8 (3-CH₃), 13.0 (2-CH₃), 28.2 (C-7), 29.4 (C-

8), 31.3 (C-10), 38.7 (C-9), 112.9 (C-6), 120.7 (C-5),

126.0 (Ph), 126.7 (Ph), 128.3 (Ph), quarternary carbon

atoms: 115.2, 122.5, 129.7, 137.3, 142.7, 146.1; Anal.

Calcd for C₁₉H₂₀N₂: C, 82.57; H, 7.29; N, 10.14. Found:

C, 82.53; H, 7.30; N, 10.10.

4.1.13. 6-Bromo-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahy-

dro-imidazo[2,1-a]isoquinoline, hydrobromide salt (19).

In a ﬂask ﬁlled with argon, 4-bromo-7-phenyl-5,6,

7,8-tetrahydro-isoquinolin-1-yl-amine (15) (6.40 g,

21.1 mmol) was dissolved in dry THF (120 ml). 3-Bro-

mobutanone (4.2 ml, 6.0 g, 40 mmol) was added and

the reaction mixture was heated to reﬂux for 90 h. A

precipitate was formed which was isolated by ﬁltration,

washed with THF, and dried in vacuo (3.0 g of pure 19,

colorless solid). The mother liquor was treated with an-

other portion of 3-bromobutanone (3.0 ml, 4.3 g,

29 mmol) and was reﬂuxed for another 75 h. A second

crop of crystals was obtained, which was isolated and

puriﬁed as described above (3.0 g of pure 19, colorless

solid). Thus, a total amount of 6.0 g (66% yield) of the

1

title compound 19 was obtained: mp 263–265 ꢁC; H

NMR (400 MHz, DMSO-d₆): d = 2.00 (m_c, 1H, 8-H_a),

2.20 (m_c, 1H, 8-H_b), 2.43 (s, 3H, 2-CH₃), 2.50 (s, 3-

CH₃), 3.00 (m_c, 4H, 7-H, 9-H, 10-H_a), 3.24 (m_c, 10-

H_b), 7.29 (m_c, 1H, Ph), 7.38 (m_c, 4H, Ph), 8.96 (s, 1H,

5-H); ¹³C NMR (100.7 MHz, DMSO-d₆): d = 7.4 (3-

CH₃), 9.3 (2-CH₃), 28.4 (C-8), 29.8 (C-7), 31.2 (C-10),

37.3 (C-9), 124.2 (C-5), 126.6 (Ph), 126.8 (Ph), 128.5

(Ph), quarternary carbon atoms: 114.3, 119.1, 121.3,

129.0, 136.8, 139.2, 144.5; HRMS (ESI) m/z

C₁₉H₂₀BrN₂[M+H]⁺Calcd: 355.0804. Found:

355.0793.

4.1.14. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-imi-

dazo[2,1-a]isoquinoline-6-carboxylic acid ethyl ester

(20).²¹In a steel autoclave ﬁlled with argon, bromo

derivative 19 (5.00 g, 11.5 mmol) was dissolved in dry

ethanol (100 ml). After addition of triethylamine

(7.5 ml, 53 mmol) a brown solution was obtained, which

was treated with palladium acetate (0.27 g, 1.2 mmol)

and triphenylphosphine (0.40 g, 1.5 mmol). The auto-

clave was pressurized with carbon monoxide (6 bar)

and heated to 115 ꢁC. The reaction mixture was kept

for 18 h at this temperature, cooled to room tempera-

ture, and poured onto a mixture of ice water (300 ml)

and dichloromethane (300 ml). The phases were sepa-

rated and the aqueous phase was extracted with dichlo-

romethane (2· 50 ml). The combined organic phases

were washed with water (100 ml), dried over sodium sul-

fate, and concentrated under reduced pressure. A brown

solid (4.5 g) was obtained, which was puriﬁed by column

chromatography [120 g of silica gel, eluant: petrol ether/

ethyl acetate = 6:4 (v/v)]. An almost colorless solid was

isolated (3.6 g, 90% yield) which was characterized as

4.1.12. 6-Bromo-2-methyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline, hydrochloride salt (18). In a

ﬂask ﬁlled with argon, 4-bromo-7-phenyl-5,6,7,8-tetra-

hydro-isoquinolin-1-yl-amine (15) (2.90 g, 9.6 mmol)

was dissolved in dry THF (25 ml). Chloroacetone

(1.30 ml, 1.51 g, 16.3 mmol) was added and the reaction

mixture was heated to reﬂux for 2.5 d. The red-brown

suspension was cooled to room temperature. The precip-

itate was isolated by ﬁltration and washed with THF

(10 ml) and diethyl ether (10 ml). Thus, the pure title

compound 18 (2.55 g, 70% yield) was obtained as a col-

orless solid. The mother liquor was treated with another

portion of chloroacetone (0.60 ml, 0.70 g, 7.5 mmol) and

reﬂuxed for 50 h. The precipitate formed was isolated by

ﬁltration and puriﬁed as described above. Another por-

tion (0.40 g, 1.1 mmol, 11% yield) of the pure title com-

pound 18 was isolated (overall yield: 81%): mp 273–

1

the pure title compound 20: mp 165–167 ꢁC; H NMR

(400 MHz, DMSO-d₆): d = 1.35 (t, J = 7.1 Hz, 3H,

COOEt), 1.87 (m_c, 1H, 8-H_a), 2.11 (m_c, 1H, 8-H_b),

2.29 (s, 3H, 2-CH₃), 2.41 (s, 3H, 3-CH₃), 2.85 (m_c, 1H,

10-H_a), 3.02 (m_c, 2H, 7-H_a, 9-H), 3.14 (m_c, 1H, 7-H_b),

3.31 (br s, H₂O, 10-H_b), 4.32 (q, J = 7.1 Hz, 2H, COO-

Et), 7.24 (m_c, 1H, Ph), 7.35 (m_c, 4H, Ph), 8.50 (s, 1H,

5-H); ¹³C NMR (100.7 MHz, DMSO-d₆): d = 7.7 (3-

1

275 ꢁC; H NMR (400 MHz, DMSO-d₆): d = 2.02 (m_c,

1H, 8-H_a), 2.22 (m_c, 1H, 8-H_b), 2.48 (s, 2-CH₃), 3.03

(m_c, 4H, 7-H, 9-H, 10-H_a), 3.36 (m_c, 10-H_b), 7.28 (m_c,

1H, Ph), 7.37 (m_c, 4H, Ph), 7.99 (s, 1H, 3-H), 9.19 (s,

1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-d₆): d = 10.2

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7655

CH₃), 13.1 (2-CH₃), 14.1 (COOEt), 27.1 (C-7), 29.4 (C-

8), 31.8 (C-10), 37.8 (C-9), 60.7 (COOEt), 125.3 (C-5),

126.1 (Ph), 126.7 (Ph), 128.3 (Ph), quarternary carbon

atoms: 115.5, 116.6, 123.5, 129.1, 139.4, 142.9, 145.9,

165.5 (COOEt). Anal. Calcd for C₂₂H₂₄N₂O₂: C,

75.83; H, 6.94; N, 8.04. Found: C, 75.67; H, 6.91; N,

7.95.

5H, Ph), 7.78 (s, 1H, CONH₂), 8.20 (s, 1H, CONH₂),

8.67 (s, 1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-d₆):

d = 7.3 (3-CH₃), 9.8 (2-CH₃), 26.8 (C-7), 28.5 (C-8),

31.2 (C-10), 37.5 (C-9), 122.4 (C-5), 126.4 (Ph), 126.8

(Ph), 128.4 (Ph), quarternary carbon atoms: 118.8,

120.7, 125.6, 130.3, 138.0, 145.1, 166.6 (CONH₂);

HRMS (ESI) m/z C₂₀H₂₂N₃O [M+H]⁺Calcd:

320.1757. Found: 320.1751.

4.1.15. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-imi-

dazo[2,1-a]isoquinoline-6-carboxylic acid (21). A solution

of ethyl carboxylate 20 (4.10 g, 11.7 mmol) in methanol

(80 ml) was treated with an aqueous solution of potas-

sium hydroxide (1.40 g, 25.0 mmol in 8 ml of water).

The slightly yellow solution was heated to 60 ꢁC for

3 h. After the methanol was removed under reduced

pressure, the reaction mixture was diluted with water

(30 ml) and extracted with ethyl acetate (2· 20 ml).

The organic phases were discarded and the aqueous

phase (initial pH value: 11) was acidiﬁed by addition

of hydrochloric acid (6 N, ﬁnal pH value: 3). A suspen-

sion was obtained which was stirred for 2 h at room

temperature. A colorless solid was isolated by ﬁltration,

which was washed with portions of water (30 ml) and

acetone (10 ml), and then dried in vacuo. The pure title

compound 21 (3.5 g) was obtained in 93% yield: mp

4.1.17. General procedure for the conversion of 2,3-

dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[2,1-a]iso-

quinoline-6-carboxylic acid (21) into carboxamides.²²

Under an argon atmosphere, a suspension of carboxylic

acid 21 (450–500 mg) in dry dichloromethane (8–15 ml)

was treated with TBTU (1.1 equiv). The reaction mix-

ture was heated to reﬂux for 1 h. The suspension was

cooled to room temperature and the respective amine

(1.0–1.1 equiv) was added slowly. Stirring was continued

for 1–3 h at room temperature and the reaction was

quenched by addition of saturated ammonium chloride

solution (5–15 ml) and dichloromethane. The biphasic

mixture was stirred for several minutes. The phases were

separated and the aqueous phase was extracted with

dichloromethane. The combined organic phases were

washed with saturated sodium bicarbonate solution

and water, dried over sodium sulfate, and concentrated

under reduced pressure. The crude product was puriﬁed

by column chromatography and/or by washing with

diethyl ether. The respective title compound was isolated

as a colorless solid.

343–345 ꢁC

(decomp.);

¹H

NMR

(400 MHz,

D₂O + NaOD): d = 1.61 (m_c, 1H, 8-H_a), 2.04 (m_c, 1H,

8-H_b), 2.21 (s, 3H, 2-CH₃), 2.22 (s, 3H, 3-CH₃), 2.62

(dd, 1H, 10-H_a), 2.84 (m_c, 1H, 9-H), 2.94 (m_c, 2H, 7-

H), 3.08 (dd, 1H, 10-H_b), 7.27 (m_c, 3H), 7.37 (m_c, 2H),

8.00 (s, 1H); ¹³C NMR (100.7 MHz, D₂O + NaOD):

d = 7.0 (3-CH₃), 11.6 (2-CH₃), 27.3 (C-7), 29.2 (C-8),

31.4 (C-10), 38.1 (C-9), 120.7 (C-5), 126.5 (Ph), 126.8

(Ph), 128.8 (Ph), quarternary carbon atoms: 117.1,

122.2, 125.7, 131.0, 137.5, 143.1, 146.4, 174.8 (COOEt);

HRMS (ESI) m/z C₂₀H₂₁N₂O₂[M+H]⁺Calcd:

321.1598. Found: 321.1591.

4.1.17.1. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline-6-carboxylic acid methylamide

(23). Preparation by condensation of carboxylic acid 21

(450 mg, 1.40 mmol) with methylamine (750 ll of a 2 M

solution in THF, 1.50 mmol) as described in the general

procedure, puriﬁcation of crude 23 was achieved by

washing with diethyl ether (15 ml): 260 mg; 56% yield;

mp 266–268 ꢁC; ¹H NMR (400 MHz, DMSO-d₆):

d = 1.86 (m_c, 1H, 8-H_a), 2.08 (m_c, 1H, 8-H_b), 2.27 (s,

3H, 2-CH₃), 2.38 (s, 3H, 3-CH₃), 2.78, 2.80 (d, m_c,

4H, CONHMe, 10-H_a), 2.89 (m_c, 2H, 7-H), 2.99 (m_c,

1H, 9-H), 3.30 (m_c, 10-H_b), 7.24 (m_c, 1H, Ph), 7.34

(m_c, 4H, Ph), 8.11 (s, 1H, 5-H), 8.30 (q, 1H, NH); ¹³C

NMR (100.7 MHz, DMSO-d₆): d = 7.8 (3-CH₃), 13.0

(2-CH₃), 25.9 (CONHMe), 26.2 (C-7), 29.3 (C-8), 31.6

(C-10), 38.2 (C-9), 120.6 (C-5), 126.1 (Ph), 126.7 (Ph),

128.3 (Ph), quarternary carbon atoms: 115.9, 122.1,

123.0, 128.2, 138.2, 142.3, 145.9, 166.9 (CONHMe);

HRMS (ESI) m/z C₂₁H₂₄N₃O [M+H]⁺Calcd:

334.1914. Found: 334.1890.

4.1.16. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo

[2,1-a]isoquinoline-6-carboxylic acid amide (22).²²Under

an argon atmosphere, a suspension of carboxylic acid 21

(450 mg, 1.40 mmol) in dry dichloromethane (18 ml)

was treated with TBTU (500 mg, 1.56 mmol). The reac-

tion mixture was heated to reﬂux for 1 h. The well-stir-

red suspension was cooled to room temperature and was

saturated with ammonia gas for 1 h. The colorless sus-

pension was poured onto a mixture of saturated ammo-

nium chloride solution (20 ml) and dichloromethane

(30 ml). The mixture was stirred for several minutes

and the pH (initial value: 10) was adjusted to 6 by addi-

tion of 6 N hydrochloric acid. The phases were sepa-

rated and the aqueous phase was extracted with

dichloromethane (20 ml). The combined organic phases

were concentrated under reduced pressure. The oily res-

idue was treated with acetone (10 ml) at which point

crystallization occurred. The solid was isolated by ﬁltra-

tion and washed with acetone (8 ml) and diethyl ether

(10 ml). After drying in vacuo, the title compound 22

was obtained in form of a colorless solid (290 mg, 65%

yield): mp 298–300 ꢁC; ¹H NMR (400 MHz, DMSO-

d₆): d = 1.94 (m_c, 1H, 8-H_a), 2.17 (m_c, 1H, 8-H_b), 2.44

(s, 3H, 2-CH₃), 2.49 (s, 3-CH₃), 2.98 (m_c, 1H, 10-H_a),

3.11 (m_c, 3H, 7-H, 9-H), 3.36 (m_c, 10-H_b), 7.32 (m_c,

4.1.17.2. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline-6-carboxylic acid dimethyla-

mide (24). Preparation by condensation of carboxylic

acid 21 (500 mg, 1.56 mmol) with dimethylamine

(0.80 ml of a 2 M solution in THF, 1.6 mmol) as de-

scribed in the general procedure, puriﬁcation of crude

24 was achieved by column chromatography [30 g of sil-

ica gel, eluant: dichloromethane/methanol = 20:1 (v/v)]

and subsequent washing with diethyl ether (8 ml):

390 mg, 72% yield; mp 239–241 ꢁC; ¹H NMR

(400 MHz, DMSO-d₆): d = 1.92 (m_c, 1H, 8-H_a), 2.08

7656

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

(m_c, 1H, 8-H_b), 2.27 (s, 3H, 2-CH₃), 2.36 (s, 3H, 3-CH₃),

2.66 (m_c, 2H, 7-H), 2.86 (s, m_c, 4H, CONMe₂, 10-H_a),

3.03 (s, br s, 4H, CONMe₂, 9-H), 3.32 (dd, 10-H_b),

7.24 (m_c, 1H, Ph), 7.34 (m_c, 4H, Ph), 8.03 (s, 1H, 5-

H); ¹³C NMR (100.7 MHz, DMSO-d₆): d = 7.8 (3-

CH₃), 13.0 (2-CH₃), 25.4 (C-7), 29.1 (C-8), 31.5 (C-10),

34.1, 38.2 (CONMe₂), 38.3 (C-9), 118.4 (C-5), 126.1

(Ph), 126.7 (Ph), 128.3 (Ph), quarternary carbon atoms:

116.1, 122.0, 123.4, 126.6, 138.2, 142.1, 145.8, 167.3

(CONMe₂). Anal. Calcd for C₂₂H₂₅N₃O: C, 76.05; H,

7.25; N, 12.09. Found: C, 75.60; H, 7.22; N, 12.02.

diethyl ether (10 ml): 450 mg, 86% yield; mp 239–

241 ꢁC (decomp.); ¹H NMR (400 MHz, DMSO-d₆):

d = 1.88 (m_c, 5H, CO-pyrrolidine, 8-H_a), 2.08 (m_c, 1H,

8-H_b), 2.27 (s, 3H, 2-CH₃), 2.37 (s, 3H, 3-CH₃), 2.69

(m_c, 2H, 7-H), 2.86 (m_c, 1H, 10-H_a), 3.03 (m_c, 1H, 9-

H), 3.22 (m_c, 3H, CO-pyrrolidine, 10-H_b), 3.47 (m_c,

2H, CO-pyrrolidine), 7.24 (m_c, 1H, Ph), 7.34 (m_c, 4H,

Ph), 8.08 (s, 1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-

d₆): d = 7.8 (3-CH₃), 13.0 (2-CH₃), 24.1, 25.5 (CO-pyr-

rolidine), 25.6 (C-7), 29.1 (C-8), 31.5 (C-10), 38.3 (C-

9), 45.2, 48.2 (CO-pyrrolidine), 118.5 (C-5), 126.1 (Ph),

126.7 (Ph), 128.3 (Ph), quarternary carbon atoms:

116.1, 123.1, 123.5, 126.5, 138.1, 142.1, 145.9, 165.6

(CO-pyrrolidine); Anal. Calcd for C₂₄H₂₇N₃O: C,

77.18; H, 7.29; N, 11.25. Found: C, 76.77; H, 7.27; N,

11.38.

4.1.17.3. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline-6-carboxylic acid (2-hydroxy-

ethyl)-amide (25). Preparation by condensation of

carboxylic acid 21 (450 mg, 1.40 mmol) with 2-amino-

ethanol (101 mg, 100 ll, 1.66 mmol) as described in the

general procedure, puriﬁcation of crude 25 was achieved

by washing with diethyl ether (15 ml): 290 mg, 57%

yield; mp 265–267 ꢁC; ¹H NMR (400 MHz, DMSO-

d₆): d = 1.86 (m_c, 1H, 8-H_a), 2.08 (m_c, 1H, 8-H_b), 2.27

(s, 3H, 2-CH₃), 2.39 (s, 3H, 3-CH₃), 2.85 (m_c, 3H, 7-

H, 10-H_a), 3.00 (m_c, 1H, 9-H), 3.25 (m_c, 10-H_b, CON-

H(CH₂)₂OH), 3.54 (m_c, 2H, CONH(CH₂)₂OH), 4.72

(br s, 1H, OH), 7.24 (m_c, 1H, Ph), 7.33 (m_c, 4H, Ph),

8.12 (s, 1H, 5-H), 8.35 (t, 1H, NH); ¹³C NMR

(100.7 MHz, DMSO-d₆): d = 7.8 (3-CH₃), 13.1 (2-

CH₃), 26.2 (C-7), 29.4 (C-8), 31.6 (C-10), 37.9 (C-9),

42.0, 59.7 (CONH(CH₂)₂OH), 120.7 (C-5), 126.1 (Ph),

126.7 (Ph), 128.3 (Ph), quarternary carbon atoms:

115.9, 122.1, 123.0, 128.1, 138.3, 142.4, 146.0, 166.7

(CONH(CH₂)₂OH); HRMS (ESI) m/z C₂₂H₂₆N₃O₂

[M+H]⁺Calcd: 364.2020. Found: 364.2006.

4.1.17.6. (2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinolin-6-yl)-morpholin-4-yl-methanone

(28). Preparation by condensation of carboxylic acid 21

(450 mg, 1.40 mmol) with morpholine (130 mg, 130 ll,

1.49 mmol) as described in the general procedure, puri-

ﬁcation of crude 28 was achieved by washing with

diethyl ether (10 ml): 440 mg, 81% yield; mp 184–

186 ꢁC; ¹H NMR (400 MHz, DMSO-d₆, 373 K):

d = 1.92 (m_c, 1H, 8-H_a), 2.12 (m_c, 1H, 8-H_b), 2.28 (s,

3H, 2-CH₃), 2.36 (s, 3H, 3-CH₃), 2.70 (m_c, 2H, 7-H),

2.92 (dd, 10-H_a), 3.06 (m_c, 1H, 9-H), 3.35 (dd, 1H, 10-

H_b), 3.47 (br s, 4H, CO-morpholine), 3.60 (br s, CO-

morpholine), 7.21 (m_c, 1H, Ph), 7.32 (m_c, 4H, Ph),

7.93 (s, 1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-d₆,

273 K): d = 7.9 (3-CH₃), 13.0 (2-CH₃), 25.6 (C-7), 29.1

(C-8), 31.4 (C-10), 38.2 (C-9), 41.7, 47.1, 65.9, 66.1

(CO-morpholine), 118.8 (C-5), 126.1 (Ph), 126.7 (Ph),

128.3 (Ph), quarternary carbon atoms: 116.1, 121.0,

123.5, 138.3, 142.1, 145.8, 166.0 (CO-morpholine). Anal.

Calcd for C₂₄H₂₇N₃O₂: C, 74.01; H, 6.99; N, 10.79.

Found: C, 73.92; H, 7.02; N, 10.86.

4.1.17.4. 2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline-6-carboxylic acid (2-methoxy-

ethyl)-amide (26). Preparation by condensation of

carboxylic acid 21 (450 mg, 1.40 mmol) with 2-methoxy-

ethylamine (112 mg, 130 ll, 1.50 mmol) as described in

the general procedure, puriﬁcation of crude 26 was

achieved by washing with diethyl ether (15 ml):

390 mg, 74% yield; mp 208–210 ꢁC; ¹H NMR

(400 MHz, DMSO-d₆): d = 1.87 (m_c, 1H, 8-H_a), 2.09

(m_c, 1H, 8-H_b), 2.27 (s, 3H, 2-CH₃), 2.38 (s, 3H, 3-

CH₃), 2.85 (m_c, 3H, 7-H, 10-H_a), 2.99 (m_c, 1H, 9-H),

3.27 (m_c, 10-H_b, CONH(CH₂)₂OMe), 3.40 (m_c, 2H,

CONH(CH₂)₂OMe), 3.46 (m_c, 2H, CONH(CH₂)₂OMe),

7.24 (m_c, 1H, Ph), 7.33 (m_c, 4 H, Ph), 8.07 (s, 1H, 5-H),

8.43 (t, 1H, NH); ¹³C NMR (100.7 MHz, DMSO-d₆):

d = 7.8 (3-CH₃), 13.1 (2-CH₃), 26.2 (C-7), 29.4 (C-8),

31.7 (C-10), 38.2 (C-9, CONH(CH₂)₂OMe), 57.9, 70.4

(CONH(CH₂)₂OMe), 120.6 (C-5), 126.1 (Ph), 126.7

(Ph), 128.3 (Ph), quarternary carbon atoms: 115.9,

121.9, 123.0, 128.0, 138.3, 142.4, 146.0, 166.6 (CON-

H(CH₂)₂OMe); HRMS (ESI) m/z C₂₃H₂₈N₃O₂

[M+H]⁺Calcd: 378.2176. Found: 378.2164.

4.1.18. (2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-imi-

dazo[2,1-a]isoquinolin-6-yl)-methanol (29). In a ﬂame-

dried ﬂask ﬁlled with argon, ethyl carboxylate 20

(2.50 g, 7.2 mmol) was dissolved in dry THF (30 ml).

At room temperature, lithium aluminium hydride

(0.40 g, 10.5 mmol) was added in small portions. Stirring

was continued for 1 h at room temperature and the reac-

tion mixture was quenched by addition of water (0.5 ml)

and a sodium hydroxide solution (15 wt%, 0.5 ml) and

diluted with more water (1.5 ml). The gray suspension

was stirred for 20 min at room temperature and was ﬁl-

tered. The ﬁlter cake was washed with THF (3· 10 ml)

and then suspended in a mixture of chloroform (30 ml)

and methanol (15 ml). The resulting slurry was stirred

for 1 h at room temperature. Insoluble material was re-

moved by ﬁltration and the ﬁlter cake was washed with

chloroform (10 ml) and methanol (10 ml). The com-

bined ﬁltrates were evaporated to dryness. The residue,

980 mg of a colorless solid (44% yield), was dried in va-

cuo and characterized as the title compound 29: mp

290–292 ꢁC, ¹H NMR (600 MHz, DMSO-d₆, 353 K):

d = 1.94 (m_c, 1H, 8-H_a), 2.14 (m_c, 1H, 8-H_b), 2.27 (s,

3H, 2-CH₃), 2.36 (s, 3H, 3-CH₃), 2.87 (m_c, 3H, 7-H,

10-H_a), 2.99 (m_c, 9-H), 3.31 (dd, 1H, 10-H_b), 4.54 (s,

4.1.17.5. (2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinolin-6-yl)-pyrrolidin-1-yl-methanone

(27). Preparation by condensation of carboxylic acid 21

(450 mg, 1.40 mmol) with pyrrolidine (107 mg, 126 ll,

1.50 mmol) as described in the general procedure, puri-

ﬁcation of crude 27 was achieved by washing with

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7657

2H, CH₂OH), 4.91 (br s, 1H, OH), 7.22 (m_c, 1H, Ph),

7.33 (m_c, 4H, Ph), 7.88 (s, 1H, 5-H); ¹³C NMR

(150.9 MHz, DMSO-d₆, 353 K): d = 7.3 (3-CH₃), 12.4

(2-CH₃), 24.2 (C-7), 29.0 (C-8), 31.2 (C-10), 38.0 (C-9),

58.9 (CH₂OH), 118.3 (C-5), 125.6 (Ph), 126.3 (Ph),

127.9 (Ph), quarternary carbon atoms: 114.8, 122.0,

124.5, 129.5, 136.5, 141.8, 145.7; HRMS (ESI) m/z

C₂₀H₂₃N₂O [M+H]⁺Calcd: 307.1805. Found: 307.1794.

126.7 (Ph), 128.3 (Ph), quarternary carbon atoms:

115.3, 120.5, 122.7, 129.7, 137.5, 142.5, 146.1; HRMS

(ESI) m/z C₂₁H₂₅N₂O [M+H]⁺Calcd: 321.1961. Found:

321.1951.

4.1.21. 2-Methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[2,

1-a]isoquinoline-6-carboxylic acid dimethylamide (32).²¹

In a steel autoclave ﬁlled with argon, bromide 18 (2.80 g,

7.4 mmol) was suspended in dry THF (10 ml). After the

addition of dimethylamine (38.0 ml of a 2 M solution in

THF, 76 mmol), palladium acetate (0.30 g, 1.3 mmol),

triphenylphosphine (1.10 g, 4.2 mmol), and triethyl-

amine (2.0 ml, 14 mmol), the autoclave was pressurized

with carbon monoxide (6 bar) and heated to 120 ꢁC.

The reaction mixture was kept for 19 h at this tempera-

ture, cooled to room temperature, and poured onto a

mixture of saturated ammonium chloride solution

(80 ml) and ethyl acetate (80 ml). The phases were sepa-

rated and the aqueous phase was extracted with ethyl ace-

tate (3· 20 ml). The combined organic phases were

washed with saturated ammonium chloride solution (2·

50 ml) and water (2· 50 ml), dried over sodium sulfate,

and concentrated under reduced pressure. A brown solid

(6 g) was obtained, which was puriﬁed by column chro-

matography [100 g of silica gel, eluant: ethyl acetate/

methanol = 100:3 (v/v)] and subsequently washed with

diethyl ether. This aﬀorded the pure carboxamide 32

(1.7 g of a colorless solid, 69% yield): mp 215–217 ꢁC;

¹H NMR (400 MHz, DMSO-d₆): d = 1.91 (m_c, 1H, 8-

H_a), 2.03 (m_c, 1H, 8-H_b), 2.30 (s, 3H, 2-CH₃), 2.66 (m_c,

2H, 7-H), 2.85, 2.88 (s, m_c, 4H, CONMe₂, 10-H_a), 3.01,

3.04 (s, m_c, 4H, CONMe₂, 9-H), 3.31 (m_c, 10-H_b), 7.24

(m_c, 1H, Ph), 7.34 (m_c, 4H, Ph), 7.58 (s, 1H, 3-H), 8.29

(s, 1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-d₆):

d = 14.1 (2-CH₃), 25.6 (C-7), 28.9 (C-8), 31.6 (C-10),

34.1, 38.2 (CONMe₂), 38.3 (C-9), 110.2 (C-3), 120.8 (C-

5), 126.1 (Ph), 126.7 (Ph), 128.3 (Ph), quarternary carbon

atoms: 122.2, 123.6, 127.8, 142.0, 143.3, 145.8, 167.0

(CONMe₂). Anal. Calcd for C₂₁H₂₃N₃O: C, 75.65; H,

6.95; N, 12.60. Found: C, 75.63; H, 6.95; N, 12.57.

4.1.19. 6-Chloromethyl-2,3-dimethyl-9-phenyl-7,8,9,10-

tetrahydro-imidazo[2,1-a]isoquinoline (30). At room tem-

perature, thionyl chloride (0.23 ml, 0.38 g, 3.2 mmol)

was added slowly to a suspension of alcohol 29

(0.95 g, 3.1 mmol) in dry dichloromethane (25 ml). The

resulting solution was stirred for 1 h at room tempera-

ture, cooled to 0 ꢁC, and treated slowly with a mixture

of saturated sodium bicarbonate solution (8 ml) and

water (5 ml). The cooling bath was removed and the bi-

phasic mixture was stirred for 10 min. The phases were

separated and the aqueous phase was extracted with

dichloromethane (10 ml). The combined organic phases

were washed with water (10 ml), dried over sodium sul-

fate, and the solvent was evaporated under reduced

pressure. The remaining brown solid was suspended in

diethyl ether (12 ml). The title compound 30 was iso-

lated by ﬁltration, washed with diethyl ether (5 ml),

and dried in vacuo (880 mg, 87% yield): mp 155–

1

157 ꢁC; H NMR (200 MHz, DMSO-d₆): d = 1.95 (m_c,

1H), 2.14 (m_c, 1H), 2.27 (s, 3H), 2.37 (s, 3H), 2.92 (m_c,

4H), 3.27 (m_c, 1H), 4.90 (m_c, 2H), 7.29 (m_c, 5 H), 8.27

(s, 1H); HRMS (ESI) m/z C₂₀H₂₂ClN₂[M+H]⁺Calcd:

325.1466. Found: 325.1459.

4.1.20. 6-Methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-

tetrahydro-imidazo[2,1-a]isoquinoline (31). Chloride 30

(500 mg, 1.54 mmol) was suspended in dry methanol

(12 ml). After the addition of sodium methylate (solu-

tion: 30 wt% in methanol, 0.56 ml, 3.0 mmol), the reac-

tion mixture was heated to 60 ꢁC. Within a period of

90 min a yellow solution was formed, which was cooled

to room temperature and poured onto a mixture of sat-

urated ammonium chloride solution (20 ml) and dichlo-

romethane (50 ml). The phases were separated and the

aqueous phase was extracted with dichloromethane (3·

5 ml). The combined organic phases were washed with

water (15 ml), dried over sodium sulfate, and concen-

trated under reduced pressure. An oily residue

(520 mg) was isolated, which was puriﬁed by column

chromatography [20 g of silica gel, eluant: dichloro-

methane/methanol = 20:1 (v/v)]. Evaporation of the cor-

responding fractions aﬀorded an oily residue (380 mg),

which was crystallized from diethyl ether (3 ml). The ti-

tle compound 31 was isolated by ﬁltration, washed with

diethyl ether (1 ml), and dried in vacuo (210 mg of a col-

orless solid, 44% yield): mp 113–114 ꢁC; ¹H NMR

(400 MHz, DMSO-d₆): d = 1.90 (m_c, 1H, 8-H_a), 2.11

(m_c, 1H, 8-H_b), 2.26 (s, 3H, 2-CH₃), 2.36 (s, 3H, 3-

CH₃), 2.80 (m_c, 3H, 7-H, 10-H_a), 2.96 (m_c, 1H, 9-H),

3.25 (m_c, s, 10-H_b, CH₂OCH₃), 4.44 (s, 2H, CH₂OCH₃),

7.24 (m_c, 1H, Ph), 7.33 (m_c, 4 H, Ph), 7.98 (s, 1H, 5-H);

¹³C NMR (100.7 MHz, DMSO-d₆): d = 7.8 (3-CH₃),

13.0 (2-CH₃), 24.7 (C-7), 29.3 (C-8), 31.6 (C-10), 38.3

(C-9), 57.2, 70.0 (CH₂OMe), 120.5 (C-5), 126.1 (Ph),

4.1.22. 3-Bromo-2-methyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline-6-carboxylic acid dimethyla-

mide (33). 7,8,9,10-Tetrahydro-imidazo[2,1-a]isoquinoline

32 (350 mg, 1.05 mmol) was dissolved in dry dichloro-

methane (8 ml). The solution was cooled to ꢀ75 ꢁC

and a suspension of N-bromosuccinimide (195 mg,

1.10 mmol) in dichloromethane (6 ml) was added over

a period of 10 min. The reaction mixture was stirred

for 1 h at ꢀ75 ꢁC and was then quenched by addition

of saturated sodium bicarbonate solution (8 ml). The

phases were separated and the aqueous phase was ex-

tracted with dichloromethane (2· 5 ml). The combined

organic phases were washed with water (10 ml), dried

over sodium sulfate, and concentrated under reduced

pressure. The foamy, colorless residue (500 mg) was

crystallized from diethyl ether (10 ml). The pure bromo

derivative 33 (385 mg, 89% yield) was isolated as a col-

orless solid: mp 166–168 ꢁC; ¹H NMR (400 MHz,

DMSO-d₆): d = 1.94 (m_c, 1H, 8-H_a), 2.09 (m_c, 1H, 8-

H_b), 2.32 (s, 3H, 2-CH₃), 2.69 (m_c, 2H, 7-H), 2.85,

2.89 (s, m_c, 4H, CONMe₂, 10-H_a), 3.03 (s, m_c, 4H,

CONMe₂, 9-H) 3.33 (m_c, 10-H_b), 7.25 (m_c, 1H, Ph),

7658

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7.35 (m_c, 4H, Ph), 8.06 (s, 1H, 5-H); ¹³C NMR

(100.7 MHz, DMSO-d₆): d = 13.3 (2-CH₃), 25.5 (C-7),

28.8 (C-8), 31.0 (C-10), 34.2, 38.1 (CONMe₂), 38.1 (C-

9), 118.4 (C-5), 126.2 (Ph), 126.7 (Ph), 128.3 (Ph), quar-

ternary carbon atoms: 123.8, 124.4, 128.8, 140.8, 143.5,

145.6, 166.4 (CONMe₂). Anal. Calcd for C₂₁H₂₂BrN₃O:

C, 61.17; H, 5.38; N, 10.19; Br, 19.38. Found: C, 61.24;

H, 5.38; N, 10.16; Br, 19.29.

CH₂OH), 7.24 (m_c, 1H, Ph), 7.34 (m_c, 4H, Ph), 8.12

(s, 1H, 5-H); ¹³C NMR (100.7 MHz, DMSO-d₆):

d = 13.0 (2-CH₃), 25.5 (C-7), 29.0 (C-8), 31.4 (C-10),

34.1, 38.2 (CONMe₂), 38.3 (C-9), 51.4 (CH₂OH), 119.2

(C-5), 126.1 (Ph), 126.7 (Ph), 128.3 (Ph), quarternary

carbon atoms: 120.8, 122.1, 123.6, 127.9, 139.7, 142.7,

145.8, 167.1 (CONMe₂); HRMS (ESI) m/z C₂₂H₂₆N₃O₂

[M+H]⁺Calcd: 364.2020. Found: 364.2003.

4.1.23. 3-Formyl-2-methyl-9-phenyl-7,8,9,10-tetrahydro-

imidazo[2,1-a]isoquinoline-6-carboxylic acid dimethyla-

mide (34). Under an argon atmosphere at a temperature

of 0 ꢁC, phosphorus oxychloride (0.33 ml, 0.54 g,

3.5 mmol) was added dropwise to dry DMF (3.5 ml).

After stirring the pink solution for 90 min at room tem-

perature, a solution of 7,8,9,10-tetrahydro-imidazo[2,1-

a]isoquinoline 32 (800 mg, 2.4 mmol) in dry DMF

(11 ml) was slowly added. The resulting red solution

was stirred for 1 h at room temperature and then for

3 h at 60 ꢁC. The reaction mixture was cooled to room

temperature, poured onto a mixture of ice water

(20 ml) and dichloromethane (20 ml), and neutralized

by addition of 25% aqueous ammonia solution. The

phases were separated and the aqueous phase was ex-

tracted with dichloromethane (3· 10 ml). The combined

organic phases were washed with water (4· 10 ml), dried

over sodium sulfate, and concentrated under reduced

pressure. The colorless residue (1.1 g) was puriﬁed by

column chromatography [40 g of silica gel, eluant: ethyl

acetate/methanol = 20:1 (v/v)]. The composition of the

obtained slightly red solid (680 mg, 78%, mp 205–

207 ꢁC) was determined by ¹H NMR spectroscopy.

The sample consisted of aldehyde 34 along with 9 wt%

of untransformed starting material 32: ¹H NMR

(200 MHz, CDCl₃): d = 2.00 (m_c, 1H), 2.25 (m_c, 1H), 2.70

(s, 3H), 2.92, 2.95, 3.00, 3.17 (m_c, s, m_c, s, 10H), 3.57 (m_c,

1H), 7.31 (m_c), 9.30 (s, 1H), 9.98 (s, 1H); HRMS (ESI)

m/z C₂₂H₂₄N₃O₂[M+H]⁺Calcd: 362.1863. Found: 362.1850.

4.2. Biochemistry

4.2.1. Determination of inhibitory activity in a competitive

binding assay against H⁺/K⁺-ATPase from hog gastric

mucosa. Given data are the mean IC₅₀values from 2 to

3 independent determinations. The malachite green as-

say modiﬁed from Yoda, A.; Hokin, L. E. (Biochem.

Biophys. Res. Commun. 1970, 40, 880–886) was used

for the determination of H⁺/K⁺-ATPase IC₅₀: Lanzetta,

P. A.; Alvarez, L. J.; Reinach, P. S.; Candia, O. A. Anal.

Biochem. 1979, 100, 95–97. Pipes [piperazine-1,4-bis(2-

ethanesulfonic acid)], sucrose, nigericin, Na–ATP, and

malachite green were purchased from Sigma–Aldrich;

Tris [Tris(hydroxymethyl)aminomethane], KCl, and

ammoniumheptamolybdate tetrahydrate from Merck;

and MgCl₂from Fluka. Final assay concentrations:

4 mM Pipes/8 mM Tris buﬀer, pH 7.4, 0.25 M sucrose,

1 mM KCl, 1 mM MgCl₂, 0.5–1 lg/100 ll nigericin

(1:1 ratio with enzyme), 0.5–1 lg/100 ll enzyme (depen-

dent on K⁺-stimulated, speciﬁc activity), and 1 mM Na–

ATP (high grade), reaction volume: 101 ll. Preparation

of malachite green reagent: two parts of malachite green

stock solution (1.2 M in H₂O, protected from light and

used within 12 weeks) was mixed with one part of

ammoniumheptamolybdate tetrahydrate stock solution

(42 g/l in 4 N HCl) and kept for 30 min at room temper-

ature prior to use. A Pipes/Tris buﬀer based solution

with sucrose and MgCl₂was prepared. Nigericin and

enzyme were added to reach the ﬁnal concentrations

mentioned above. Eighty microliters per well of this

mixture was placed into 96-well ﬂat bottom plates

(clear, polystyrol, Greiner bio-one). Ten microliters

per well of KCl (1 mM ﬁnal) was used for stimulation

of the H⁺/K⁺-ATPase activity. Test substances were dis-

solved as 10 mM solutions in 100% DMSO. One micro-

liter of substance solution was added in dilutions

ranging from 1 · 10^ꢀ4to 1 · 10^ꢀ9M (ﬁnal). The enzy-

matic reaction was started by the addition of 10 ll

ATP (1 mM ﬁnal). The assay was incubated for

30 min at room temperature. The reaction was stopped

by the addition of 150 ll of malachite green reagent and

incubated for another 15 min prior to photometric read-

ing of the plate at 680 nm in a PowerWave HT Micro-

plate spectral photometer (BioTek). The results were

analyzed with GraphPad Prism software (Version

4.02) to calculate IC₅₀values by sigmoidal curve ﬁtting.

‘Enzyme’ refers to H⁺/K⁺-ATPase-containing vesicles

prepared from hog gastric mucosa as described in Ra-

bon, E. C.; Im, W. B.; Sachs, G. Methods Enzymol.

1988, 157, 649–654.

4.1.24. 3-Hydroxymethyl-2-methyl-9-phenyl-7,8,9,10-tet-

rahydro-imidazo[2,1-a]isoquinoline-6-carboxylic acid

dimethylamide (35). Aldehyde 34 (300 mg containing

9 wt% of 32, 0.83 mmol) was dissolved in dry methanol

(10 ml). Sodium borohydride (40 mg, 1.06 mmol) was

added in small portions. A clear solution was obtained,

which was stirred for 30 min at room temperature and

then poured onto a mixture of saturated ammonium

chloride solution (10 ml) and dichloromethane (20 ml).

The phases were separated and the aqueous phase was

extracted with dichloromethane (3· 5 ml). The com-

bined organic phases were washed with saturated

ammonium chloride solution (10 ml) and water

(10 ml), dried over sodium sulfate, and concentrated un-

der reduced pressure. The colorless residue (300 mg) was

puriﬁed by column chromatography [30 g of silica gel,

eluant: dichloromethane/methanol = 100:3 (v/v)]. The

pure title compound (190 mg, 63% yield) was isolated

as

a

colorless solid: mp 385–388 ꢁC; ¹H NMR

(400 MHz, DMSO-d₆): d = 1.94 (m_c, 1H, 8-H_a), 2.10

(m_c, 1H, 8-H_b), 2.31 (s, 3H, 2-CH₃), 2.67 (m_c, 2H, 7-

H), 2.86, 2.89 (s, m_c, 4H, CONMe₂, 10-H_a), 3.02 (s,

4H, CONMe₂, 9-H), 3.31 (m_c, 10-H_b), 4.74 (d,

J = 4.8 Hz, 2H, CH₂OH), 5.05 (t, J = 5.1 Hz, 1H,

4.2.2. ¹⁴C-Dimethylaminopyridine accumulation in intact

gastric glands. Gastric acid secretion is stimulated by

gastrin, histamine and acetylcholine via the receptors

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

7659

on the parietal or the enterochromaﬃn-like cell. These

physiologic stimuli inﬂuence the intracellular cyclic

AMP and Ca²⁺levels, thus leading to relocation and

activation of H⁺/K⁺-ATPase. Instead of the physiologic

agonists, the membrane-permeant dibutyryl-cyclic AMP

was used to stimulate receptor-independent acid secre-

tion in isolated gastric glands. Accumulation of the

weak base ¹⁴C-dimethylaminopyridine (¹⁴C-AP) in the

acidic compartment of the canaliculi serves as an indi-

rect measure of acid secretion and forms the basis of

measurement of acid secretion in this in vitro model of

the mammalian stomach. Intact gastric glands were pre-

pared from anesthesized New Zealand rabbits (weight

2–3 kg) by high-pressure perfusion of the stomach, sep-

aration of the fundic mucosa, and subsequent collage-

nase digestion of fragments of the mucosa (Berglindh,

T; Helander, H. F.; Obrink, K. J. Acta Physiol. Scand.

1976, 97, 401–414; Berglindh, T.; Obrink, K. J. Acta

Physiol. Scand. 1976, 96, 150–159). After the gastric

glands were washed several times, they were suspended

in Krebs–Henseleit solution containing 2 mg/ml rabbit

serum albumin and 2 mg/ml glucose. The glands were

incubated for 30 min at 37 ꢁC in a shaker bath

(200 osc/min) in the presence of 0.125 lM ¹⁴C-AP

(113 lCi/lmol) at pH 7.4. The glands were stimulated

with 1 mM dibutyryl cAMP in the absence or presence

of the corresponding inhibitor (concentration range

3 nM–100 lM). The reaction was stopped by centrifuga-

tion (10 s at 20,000g). After centrifugation, the accumu-

lation of ¹⁴C-AP in the glands was calculated as follows:

radioactivity was measured in an aliquot of the superna-

tant (200 ll) and in the precipitate after dissolution in

1 ml of 1 N NaOH. In order to calculate the amount

of protein, the Eppendorf tubes were weighed empty,

with protein (wet weight) and with freeze-dried protein

(dry weight). This ratio of supernatant and pellet protein

radioactivity was used to calculate the accumulation of

¹⁴C-AP in the glands. The inhibitor concentration re-

quired to achieve 50% inhibition (IC₅₀) of ¹⁴C-AP accu-

mulation was determined by ﬁtting the equation for the

expected inhibition pattern to the data points.

4.3.3. Determination of distribution coeﬃcients. The dis-

tribution coeﬃcients between 1-octanol and aqueous

KCl solution were determined at 25 ꢁC by potentiomet-

ric titrations in the pH range of 2.0–11.0. The titrations

were performed in mixtures of 0.15 mol/l KCl solution

and water saturated 1-octanol with varying 1-octanol

portions using 0.5 mol/l KOH and HCl as titrants,

respectively. The logD values in dependence of pH were

obtained by least squares ﬁtting of the experimental data

to a theoretical function of the distribution coeﬃcient D

(ReﬁnementPro2): Comer, J.; Tam, K.; Lipophilicity

proﬁles: Theory and Measurement, in Pharmakokinetic

Optimization in Drug Research: Biological, Physicochem-

ical and Computational Strategies, Testa, B.; van de

Waterbeemd, H.; Folkers, G.; Guy, R., Eds.; VHCA:

Zurich, 2001, pp 275–304.

Acknowledgments

We are grateful to Ms. C. Jecke, Ms. G. Munch, Ms. M.

¨

David, Ms. I Hartig-Beecken, and Ms. B. Bo¨ssenecker

for technical assistance.

Supplementary data

NMR spectra (¹H, ¹³C, H,C-HMBC) of all target

compounds. This material is available free of charge

via the Internet at http://www.sciencedirect.com. Sup-

plementary data associated with this article can be

found, in the online version, at doi:10.1016/

j.bmc.2007.08.065.

References and notes

1. NIH Publication No. 03-0882, June 2003, http://digestive.

niddk.nih.gov/ddiseases/pubs/gerd/index.htm.

2. Locke, G. R., 3rd; Talley, N. J.; Fett, S. L.; Zinsmeister,

A. R.; Melton, L. J., 3rd Gastroenterology 1997, 112,

1448–1456.

4.3. Physical chemistry

3. NIH Publication No. 05-4225, October 2004, http://

digestive.niddk.nih.gov/ddiseases/pubs/hpylori/index.htm.

4. Lethbridge-Cejku, M.; Vickerie, J. Summary health sta-

tistics for U.S. adults: National Health Interview Survey,

2003. National Center for Health Statistics, Vital Health

Stat. 2005, 10.

5. (a) Parsons, M. E.; Keeling, D. J. Expert Opin. Investig.

Drugs 2005, 14, 411–421; (b) Fass, R.; Shapiro, M.; Dekel,

R.; Sewell, J. Aliment. Pharmacol. Ther. 2005, 22, 79–94;

(c) Vakil, N. Aliment. Pharmacol. Ther. 2004, 19, 1041–

1049.

4.3.1. General. The determination of dissociation con-

stants (pK_a) and lipophilicity [logP, logD(pH 7.4)] was

performed on a Sirius GL pK_aanalyzer speciﬁcally de-

signed for pH-metric pK_aand 1-octanol/water partition

coeﬃcient measurements (Sirius Analytical Instruments

Ltd, Forest Row, UK).

4.3.2. Determination of dissociation constants. The pK_a

values of the investigated compounds were determined

by potentiometric co-solvent titrations in 0.15 mol/l

KCl solutions in the pH range of 2.0–11.0 at 25 ꢁC using

methanol as co-solvent in varying portions and 0.5 mol/l

KOH and HCl as titrants, respectively. Linear extrapo-

lation to 0% co-solvent-content was performed by the

Yasuda-Shedlovsky plot method implemented in the

software ReﬁnementPro 2 from SIRIUS (Avdeef, A.;

Box, K. J.; Comer, J. E. A., Gilges, M.; Hadley, M.;

Hibbert, C.; Patterson, W.; Tam, K. Y. J. Pharm. Bio-

med. Anal. 1999, 20, 631–641).

6. Andersson, K.; Carlsson, E. Pharmacol. Ther. 2005, 108,

294–307.

7. Kaminski, J. J.; Bristol, J. A.; Puchalski, C.; Lovey, R. G.;

Elliott, A. J.; Guzik, H.; Solomon, D. M.; Conn, D. J.;

Domalski, M. S.; Wong, S.-C.; Gold, E. H.; Long, J. F.;

Chiu, P. J. S.; Steinberg, M.; McPhail, A. T. J. Med.

Chem. 1985, 28, 876–892.

8. Kaminski, J. J.; Hilbert, J. M.; Pramanik, B. N.; Solomon,

D. M.; Conn, D. J.; Rizvi, R. K.; Elliott, A. J.; Guzik, H.;

Lovey, R. G.; Domalski, M. S.; Wong, S.-C.; Puchalski,

C.; Gold, E. H.; Long, J. F.; Chiu, P. J. S.; McPhail, A. T.

J. Med. Chem. 1987, 30, 2031–2046.

7660

A. M. Palmer et al. / Bioorg. Med. Chem. 15 (2007) 7647–7660

9. Kaminski, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R.

17. (a) Boger, D. L.; Panek, J. S.; Yasuda, M. Organic

Syntheses 1988, 66, 142–150; (b) Schmidt, P.; Druey, J.

Helv. Chim. Acta 1955, 38, 1560–1564.

K.; Conn, D. J.; Elliott, A. J.; Lovey, R. G.; Guzik, H.;

Chiu, P. J. S.; Long, J. F.; McPhail, A. T. J. Med. Chem.

1989, 32, 1686–1700.

18. Glyoxal was prepared by phosphorous pentoxide-medi-

ated cleavage of the corresponding trimer and subsequent

destillation, see Wang, Y.; Arif, A. M.; Gladysz, J. A.

Organometallics 1994, 13, 2164–2169, and Section 4.

19. Separation of the product from regioisomeric 7-phenyl-

5,6,7,8-tetrahydroisoquinolin-3-amine (16–21%) was

accomplished by column chromatography (see Section 4).

20. Best results were obtained when the formed imidazo[1,2-

a]pyridine salt was removed by ﬁltration and when the

corresponding a-halo ketone was added in several por-

tions (see Section 4).

10. Folded conformation: phenyl ring directed toward and

over the imidazo[1,2-a]pyridine ring system; extended

conformation: phenyl ring oriented out and away from

the heterocyclic nucleus.

11. Gold, E. H.; Kaminski, J. J.; Puchalski, D. US 4468400.

12. Brehm, C.; Chiesa, M. V.; Zimmermann, P. J.; Buhr, W.;

Simon, W. A.; Kromer, W.; Postius, S.; Palmer, A. WO

2005/090346.

13. Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B.

M. J. Med. Chem. 1991, 34, 533–541.

14. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179–

2182.

15. White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32,

213–214.

16. (a) Krass, D.; Paudler, W. W. Synthesis 1974, 351–352; (b)

Paudler, W. W.; Barton, J. M. J. Org. Chem. 1966, 31,

1720–1722.

21. (a) Head, R. A.; Ibbotson, A. Tetrahedron Lett. 1984, 25,

5939–5942; (b) Horino, H.; Sakaba, H.; Arai, M. Synthesis

1989, 715–718.

22. TBTU = O-(1H-benzotriazol-1-yl)-N,N,N⁰,N⁰-tetramethyl-

uronium tetraﬂuoroborate, see, for example, Montalbetti,

C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–

10852.

Article Doi

Preparation of tetrahydroimidazo[2,1-a]isoquinolines and their use as inhibitors of gastric acid secretion

DOI: 10.1016/j.bmc.2007.08.065

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.bmc.2007.08.065

Full text of DOI:10.1016/j.bmc.2007.08.065

Products guided by the article

R&D Labs maybe for 865458-58-8

Relevant to this article

Hot Product