Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover σ1 ligands

DOI: 10.1021/jm990135j

Source and publish data:

Journal of Medicinal Chemistry p. 3965 - 3970 (1999)

Update date:2022-07-31

Topics:

Authors:

Nakazato, Atsuro

Kumagai, Toshihito

Ohta, Kohmei

Chaki, Shigeyuki

Okuyama, Shigeru

Tomisawa, Kazuyuki

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Article abstract of DOI:10.1021/jm990135j

The synthesis and structure-activity relationships (SAR) of 1-alkyl-2- phenylethylamine derivatives 5-8 designed from N,N-dipropyl-2-[4-methoxy-3- (2-phenylethoxy)phenyl]ethylamine hydrochloride (1, NE-100) are presented. The SAR between compound 1 and 1-alkyl-2-phenylethylamine derivatives suggested that the alkyl group on the 1-position carbon of 2-[4-methoxy-3-(2- phenylethyl)phenyl]ethylamine derivatives played the role of one of the propyl groups on the aminic nitrogen of compound 1. (-)-N-Propyl-1-butyl-2- [4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride ((-)-6d, NE-537) and (-)-N-propyl-1-(3-methybutyl)-2-[4-methoxy-3-(2- phenylethoxy)phenyl]ethylamine hydrochloride ((-)-6i, NE-535), typical compounds in this series, have potent and selective σ₁ affinity.

Full text of DOI:10.1021/jm990135j

J . Med. Chem. 1999, 42, 3965-3970

3965

Syn th esis a n d SAR of 1-Alk yl-2-p h en yleth yla m in e Der iva tives Design ed fr om

N,N-Dip r op yl-4-m eth oxy-3-(2-p h en yleth oxy)p h en yleth yla m in e To Discover σ₁

Liga n d s

Atsuro Nakazato,* Toshihito Kumagai, Kohmei Ohta, Shigeyuki Chaki, Shigeru Okuyama, and

Kazuyuki Tomisawa

Medicinal Research Laboratories, Taisho Pharmaceutical Company Ltd., 1-403 Yoshino-cho, Ohmiya,

Saitama 330-8530, J apan

Received March 22, 1999

The synthesis and structure-activity relationships (SAR) of 1-alkyl-2-phenylethylamine

derivatives 5-8 designed from N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine

hydrochloride (1, NE-100) are presented. The SAR between compound 1 and 1-alkyl-2-

phenylethylamine derivatives suggested that the alkyl group on the 1-position carbon of 2-[4-

methoxy-3-(2-phenylethyl)phenyl]ethylamine derivatives played the role of one of the propyl

groups on the aminic nitrogen of compound 1. (-)-N-Propyl-1-butyl-2-[4-methoxy-3-(2-phen-

ylethoxy)phenyl]ethylamine hydrochloride ((-)-6d , NE-537) and (-)-N-propyl-1-(3-methybutyl)-

2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride ((-)-6i, NE-535), typical

compounds in this series, have potent and selective σ₁affinity.

Ch a r t 1

In tr od u ction

Since Hellewell and Bowen¹described σ₁and σ₂

receptor subtypes, several σ₁and σ₂ligands have been

presented.^2-7Molecular cloning experiments^8,9have

suggested that σ binding protein did not seem to be

related to cytochrome P-450 and neuropeptide Y recep-

tor.^10,11However, the molecular properties and signaling

mechanisms mediated through σ receptors have not

been fully elucidated. Among the several known σ₁

ligands, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-

phenyl]ethylamine hydrochloride (1) (Chart 1) has

moderate selectivity at the σ₁receptor over the σ₂

receptor¹²but is a useful ligand, since it is easily labeled

by tritium¹³and can be used to study biochemical effects

selectively mediated by the σ₁receptor.^14,15Selective and

high-affinity σ₁ligands containing a methoxy group to

be labeled with tritium are more useful than compound

1 for determining the physiological and clinical signifi-

cance of σ₁ligands. Characterization of compound 1 and

its derivatives 2-4¹⁶yielded three suggestions for

discovering σ ligands: (1) one propyl group of compound

1 might be required for formation of the fundamental

conformation for interaction with σ receptors, since

compound 3 has moderate σ affinity whereas compound

2 has none; (2) another propyl group of compound 1

might play an important role in interacting with the

hydrophobic pocket of σ receptors, since compound 1 has

about 30 times the σ affinity of compound 3; (3) it might

be best if the two propyl groups are located in different

spaces to yield high σ affinity, since compound 4

containing a cyclic amine has moderate σ affinity (Chart

1).

anticipated that R¹and/or R²of the derivatives 5-8

would play the role of the one or two propyl groups on

the aminic nitrogen of compound 1 (Chart 1). In this

paper, we present the synthesis and SAR of novel

1-alkyl-2-phenylethylamine derivatives 5-8.

Ch em istr y

The processes for preparing 1-alkyl-2-phenylethyl-

amine derivatives 5-8 (cf. Table 1) are depicted in

generic Schemes 1 and 2.

In light of these suggestions, our interest focused on

1-alkyl-2-phenylethylamine derivatives 5-8, since we

Derivative 10 is prepared from benzaldehyde 9¹⁶by

standard synthetic procedures, modified Horner-Em-

mons condensation¹⁷of compound 9, hydrogenation of

* Correspondence to: Atsuro Nakazato, Ph.D. Tel: +81 48 663 1111.

Fax: +81 48 652 7254. E-mail: S10968@ccm.taisho.co.jp.

Published on Web 09/03/1999

3966 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19

Ta ble 1. 1-Alkyl-2-phenylethylamine Derivatives: Physical Data

Nakazato et al.

compd

R¹

n-Pr

n-Bu

n-Pen

n-Hex

n-Hep

n-Oct

i-Pen

R²

R³

R⁴

salt

method^a

mp (°C)

analysis^b

C₂₃H₃₁NO₄

(()-10a

(()-10b

(()-10c

(()-10d

(()-10e

(()-10f

(()-10g

(()-10h

(()-10i

(()-5a

(()-5b

(()-5c

(()-5d

(()-5e

(()-5f

(()-5g

(()-5h

(()-5i

(()-6a

(()-6b

(()-6c

(()-6d

(+)-6d

(-)-6d

(()-6e

(()-6f

(()-6g

(()-6h

(()-6i

(+)-6i

(-)-6i

(()-7a

(()-7b

(()-7c

(()-7d

(()-7e

(()-7f

(()-7g

(()-7h

Boc

n-Pr

oil

n-Pr

88.5-89.5^d

89-90^d

101.5-102^d

91.5-92.5^d

85-86^d

82.5-83.5^d

805-81^d

103-104^d

88-90.5^e

127.5-128.5^e

126.5-127.5^f

oil

C₂₄H₃₃NO₄

C₂₅H₃₅NO₄

C₂₆H₃₇NO₄

C₂₇H₃₉NO₄

C₂₈H₄₁NO₄

C₂₉H₄₃NO₄

C₃₀H₄₅NO₄

C₂₇H₃₉NO₄

HCl

C₁₈H₂₃NO₂‚HCl‚1/4TFA

C₁₉H₂₅NO₂‚HCl‚1/20TFA

C₂₀H₂₇NO₂‚HCl‚1/2TFA

n-Pr

n-Bu

n-Pen

n-Hex

n-Hep

n-Oct

i-Pen

₂₁H₂₉NO₂‚1/7CHCl₃

C₂₂H₃₁NO₂‚HCl

₂₃H₃₃NO₂‚1/20CHCl₃

HCl

120.5-122^f

oil

C₂₄H₃₅NO₂‚1/15CHCl₃

C₂₂H₃₁NO₂‚1/20CHCl₃

C₂₂H₃₁NO₂‚HCl

C₂₁H₂₉NO₂‚HCl

C₂₂H₃₁NO₂‚1/4CHCl₃

HCl

91.5-92^g

79-80.5^h

oil

n-Pr

oil

C₂₃H₃₃NO₂‚1/20CHCl₃

C₂₄H₃₅NO₂‚1/10CHCl₃

C₂₄H₃₅NO₂‚HCl

n-Bu

n-Pen

n-Hex

n-Hep

n-Oct

i-Pen

HCl

82.5-83.5^h

83-84^h

93-94^h

oil

C₂₄H₃₅NO₂‚HCl

C₂₅H₃₇NO₂‚HCl

C₂₆H₃₉NO₂‚1/15CHCl₃

oil

C₂₇H₄₁NO₂‚1/15CHCl₃

C₂₈H₄₃NO₂‚1/20CHCl₃

C₂₅H₃₇NO₂‚HCl

HCl

124-125^h

98-99^h

99-100^h

oil

C₂₅H₃₇NO₂‚HCl

n-Pr

C₂₄H₃₅NO₂

n-Pr

oil

C₂₅H₃₇NO₂‚1/10CHCl₃

C₂₆H₃₉NO₂‚1/15CHCl₃

C₂₇H₄₁NO₂‚1/20CHCl₃

C₂₈H₄₃NO₂‚HCl

n-Bu

n-Pen

n-Hex

n-Hep

n-Oct

n-Pr

HCl

C₂₉H₄₅NO₂‚1/15CHCl₃

C₃₀H₄₇NO₂‚1/20CHCl₃

C₃₁H₄₉NO₂‚1/20CHCl₃

C₂₃H₃₃NO₂‚C₄H₄O₄

Fum^c

167.5-168.5ⁱ

Methods A-E are described in the text. Elemental analyses for all compounds were within (0.4% of the theoretical values for the

indicated formula. Analyses were performed for all elements except O. ^cFumaric acid.

Recrystallization solvents are depicted: ^dhexane,

d-h

^eCH₂Cl₂-diisopropyl ether, ^fdiisopropyl ether, ^gdiisopropyl ether-hexane, ^htoluene-hexane. ⁱPrecipitation solvents are depicted: ⁱacetone-

diethyl ether.

the double bond over PtO₂, hydrolysis of the ester, and

modified Curtius reaction of phenylpropionic acids using

diphenyl phosphorazidate and tert-butyl alcohol¹⁸(method

A). Deprotection of the tert-butoxycarbonyl group (Boc)

of derivative 10 gives the primary amine 5 (method B).

Treatment of compound 5 with 1.5-2.0 equiv of propyl

bromide in N,N-dimethylformamide (DMF) containing

potassium carbonate gives derivatives 6 and 7, which

can easily be separated by silica gel chromatography

(method C). Optical derivative 6 is prepared by resolu-

tion of racemic derivative 5 using (+)- or (-)-mandelic

acid followed by N-alkylation using 1.0-1.2 equiv of

propyl bromide and potassium carbonate in DMF

(method D) (Scheme 1).

Resu lts a n d Discu ssion

Binding data for compounds 5-8 are shown in Table

2, with the known data for compounds 1-4.¹⁶

Compounds with substitution of alkyl groups of C4-

C6 length (R¹), (()-5d -(()-5f and (()-5i, exhibited

higher σ affinity than compounds with substitution of

shorter or longer alkyl groups, (()-5a -(()-5c or (()-5g

and (()-5h . The potencies of compounds (()-5d -(()-5f

and (()-5i were in accord with that of N-propyl com-

pound 3. This suggests that the length of C4-C6 for R¹

best plays the role of one propyl group of 1, enabling

formation of the fundamental conformation for interac-

tion with σ receptors or interaction with the hydrophobic

pocket of σ receptors.

To obtain compound 8, compound 11¹⁶is treated with

allylmagnesium bromide followed by hydrogenation of

the two allyl groups to afford the desired compound.

Direct reaction of propylmagnesium bromide with com-

pound 11 did not yield compound 8 (Scheme 2).

N-Propylated compounds (()-6a -(()-6i had much

higher σ affinity than the compounds (()-5a -(()-5i,

respectively. This finding suggests that the two alkyl

groups, R¹and N-propyl groups, are required for high

Synthesis and SAR of 1-Alkyl-2-phenylethylamines

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3967

Sch em e 1^a

Ta ble 2. 1-Alkyl-2-Phenylethylamine Derivatives: In Vitro

Data

IC₅₀(nM)^a

compd

R¹

R²

R³

R⁴

salt

HCl

σ₁σ₂

D₂

1^b

2^b

3^b

4^b

1.3

>1000 NT NT >1000

1.5 85 >1000

n-Pr

NT NT >1000

-(CH₂)₄- (CO₂H)₂110

(()-5a Me

(()-5b Et

HCl

>1000 NT NT NT

330

160

110

170

420

>1000 NT NT NT

130

8.0

4.5

2.1

1.5

9.0

170

1.8

(()-5c n-Pr

(()-5d n-Bu

(()-5e n-Pen

(()-5f n-Hex

(()-5g n-Hep

(()-5h n-Oct

(()-5i i-Pen

(()-6a Me

NT NT NT

HCl

NT NT NT

n-Pr

n-Pr n-Pr

n-Pr n-Pr HCl

n-Pr n-Pr

(()-6b Et

7.8 330 >1000

4.1 250 >1000

1.9 320 >1000

34 210 NT

0.7 230 >1000

2.2 110 >1000

8.1 230 >1000

NT NT NT

1.6 210 >1000

22 190 NT

0.5 200 >1000

NT NT NT

5.6 390 >1000

8.2 420 >1000

NT NT NT

(()-6c n-Pr

(()-6d n-Bu

(+)-6d n-Bu

(-)-6d n-Bu

(()-6e n-Pen

(()-6f n-Hex

(()-6g n-Hep

(()-6h n-Oct

(()-6i i-Pen

(+)-6i i-Pen

(-)-6i i-Pen

(()-7a Me

HCl

Method A: (1) R¹CH(CO₂Et)P(O)(OEt)₂, NaH, THF; (2) H₂,

5% Pd/C, EtOH; (3) NaOH, H₂O, EtOH; (4) DPPA, Et₃N, PhH and

then t-BuOH. Method B: (1) TFA-CH₂Cl₂. Method C: (1) PrBr

(1.5-2.0 equiv), K₂CO₃, DMF. Method D: (1) resolution (salt with

mandelic acid); (2) PrBr (1.0-1.2 equiv), K₂CO₃, DMF.

HCl

Sch em e 2^a

(()-7b Et

5.7

9.5

(()-7c n-Pr

(()-7d n-Bu

(()-7e n-Pen

(()-7f n-Hex

(()-7g n-Hep

(()-7h n-Oct

NT NT NT

150

230

n-Pr n-Pr

>1000 NT NT NT

n-Pr

Fum^c

IC₅₀values represent the means of 1-3 separate experiments

obtained from 10 concentrations of each compound, run in

duplicate. Variation between experiments was less than 15%. NT,

Method E: (1) allyl-MgBr, Et₂O; (2) H₂, PtO₂, AcOEt.

σ affinity in 1-alkyl-2-phenylethyamine derivatives such

as 1 and its derivatives. Among the N-propylated

compounds, compounds (()-6d , (()-6e, and (()-6i had

particularly high σ affinities, and these potencies were

approximately equal to that of compound 1. Alkyl group

of C4 or C5 length (R¹) might be preferred for playing

the role of one propyl group of compound 1 and retaining

high σ affinity of compound 1. Furthermore, compounds

(()-6d and (()-6i exhibited higher σ₁selectivity than

compound (()-6e. We also studied the relationship

between the optical isomers of compounds (()-6d and

(()-6i and affinity. The (-)-isomers, (-)-6d and (-)-6i,

had very high σ₁affinity, while the (+)-isomers, (+)-6d

and (+)-6i, exhibited approximately 50-fold reduction

in σ₁affinity. The σ₁affinities of compounds (-)-6d and

(-)-6i were about 300 and 400 times their respective

σ₂affinities.

N,N-Dipropylated compound 7 exhibited a more than

10-fold reduction in σ affinity compared to the N-

propylated compound 6, except for compounds (()-7a -

(()-7c. Notably, however, compounds (()-7a -(()-7c

were less potent than the corresponding compound 1.

This suggests that there may be steric restriction of

binding at the space of the third alkyl group. The third

not texted. Binding data presented in ref 16. ^cFumaric acid.

alkyl group could hinder binding to σ receptors, since

compound 1, a compound nonsubstituted with the third

alkyl group, exhibited the highest σ affinity among N,N-

dipropylated compounds.

With these findings, we proceeded to examine the 1,1-

dialkyl-2-phenylethylamine derivative 8 in the hope of

discovering a high-affinity σ ligand. Contrary to expec-

tation, compound 8 did not exhibit σ affinity, possibly

due to steric hindrance of the tertiary alkyl group on

the aminic nitrogen.

The above discussion about SAR of compounds 5-8

is based on van der Waals interaction between the alkyl

group (R¹and/or R²) and the hydrophobic pocket of σ

receptors. Notably, however, this discussion might not

fully elucidate the SAR of compounds 5-8, for example,

high σ₁selectivity of compounds (()-6d , (-)-6d , (()-6i,

and (-)-6i and slight difference of σ affinity between

compound 3 and (()-5d -(()-5f and (()-5i. A difference

of electron density (basicity) on the nitrogen atom

among primary (5), secondary (6), and tertiary (7, 1)

amines could influence binding, since a hydrogen bond

strongly promotes interaction between receptor and

3968 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19

Nakazato et al.

saturated brine, dried (MgSO₄), and then concentrated in

vacuo. The residue was chromatographed (hexanes/AcOEt

30:1) to obtain two isomers of ethyl 3-[4-methoxy-3-(2-phen-

ylethoxy)phenyl]-2-pentylacrylate as a colorless oil (5.39 g,

68%).

ligand. The high σ₁selectivity of compounds (()-6d , (-)-

6d , (()-6i, and (-)-6i might be due to both the van der

Waals and hydrogen bond interactions influenced by the

length of alkyl group (R¹) and the electron density on

the aminic nitrogen, respectively. The electron density

on the nitrogen of the secondary amines might be more

preferred than those of the primary and tertiary amines

for σ or σ₁affinity, since the secondary amines exhibited

slightly higher σ or σ₁affinity than the primary (3 vs

(()-5d -(()-5f and (()-5i) and tertiary ((-),(()-6d and

(-),(()-6i vs 1) amines. On the other hand, compounds

with high σ affinity (IC₅₀< 10 nM) did not exhibit

affinity for dopamine D₂receptors (IC₅₀> 1000 nM).

E-Isom er : 4.49 g (56%); H NMR (CDCl₃) δ 0.84 (3 H, t, J

) 7.0 Hz, CH₃of Pen), 1.27-1.40 (4 H, m, 2 × CH₂), 1.33 (3

H, t, J ) 7.1 Hz, CH₃of Et), 1.45-1.65 (2 H, m, CH₂), 2.52 (2

H, br t, J ) 7.9 Hz, CdCCH₂), 3.18 (2 H, t, J ) 7.6 Hz, CH₂-

Ph), 3.90 (3 H, s, CH₃O), 4.22 (2 H, t, J ) 7.6 Hz, OCH₂Bn),

4.25 (2 H, q, J ) 7.1 Hz, O₂CH₂), 6.89 (1 H, d, J ) 8.2 Hz,

ArH), 6.94 (1 H, d, J ) 1.8 Hz, ArH), 7.00 (1 H, d d, J ) 1.8,

8.2 Hz, ArH), 7.23-7.32 (5 H, m, ArH), 7.55 (1 H, br s, Cd

CH); MS (EI) m/z 396 (M⁺), 105 (100%); IR (neat) 1703, 1625,

1600, 1580, 1516, 1455 cm^-1. Anal. (C₂₅H₃₂O₄) C, H.

Z-Isom er : 0.44 g (6%); ¹H NMR (CDCl₃) δ 0.89 (3H, t, J )

6.6 Hz, CH₃of Pen), 1.13 (3 H, t, J ) 7.1 Hz, CH₃of Et), 1.26-

1.41 (4 H, m, 2 × CH₂), 1.43-1.53 (2 H, m, 2 × CH₂), 2.37 (2

H, br t, J ) 7.1 Hz, CdCCH₂), 3.15 (2 H, t, J ) 7.6 Hz, CH₂-

Ph), 3.86 (3 H, s, CH₃O), 4.11 (2 H, q, J ) 7.1 Hz, CO₂CH₂),

4.18 (2 H, t, J ) 7.6 Hz, OCH₂Bn), 6.48 (1 H, br s, CdCH),

6.77-6.85 (3 H, m, ArH), 7.20-7.31 (5 H, m, ArH); MS (EI)

m/z 396 (M⁺), 105 (100%); IR (neat) 1714, 1603, 1582, 1515,

1455, 1443 cm^-1. Anal. (C₂₅H₃₂O₄) C, H.

Con clu sion s

Our findings suggested that the 1-position alkyl group

of 1-alkyl-2-phenylalkylamine derivatives played the

role of one of the propyl groups on the aminic nitrogen

ofN,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-

ethylamine hydrochloride (1) and that there might be

steric restriction for the third alkyl group at the 1-posi-

tion (R²). The 1-alkyl-2-phenylalkylamine derivatives

containing one alkyl group on the 1-position carbon and

one propyl group on the aminic nitrogen had high affin-

ity for σ receptors. Among the derivatives, (-)-N-propyl-

1-butyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethyl-

amine hydrochloride ((-)-6d ) and (-)-N-propyl-1-(3-

methybutyl)-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-

ethylamine hydrochloride ((-)-6i) may be useful for

examining the physiological and clinical significance of

the σ₁receptor, since they are potent and selective σ₁

ligands, and the [O-methyl-³H]-compound (-)-6d or (-)-

6i could be produced by the same preparation procedure

as that for [O-methyl-³H]-compound 1.

Mixtu r e of E- a n d Z-isom er s: 0.44 g (6%).

A suspension of the mixture of E- and Z-isomers in ethyl

3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-pentylacrylate (5.16

g, 13.0 mmol) and 5% Pd/C (0.52 g) in ethanol (25 mL) was

stirred under an atmosphere of hydrogen. After the theoretical

amount of hydrogen was taken up, the suspension was filtered

through Celite. To the filtrate was added a solution of KOH

(3.17 g, 56.6 mmol) in water (5 mL), and the resulting solution

was stirred overnight. The reaction mixture was concentrated

in vacuo, and the residue was partitioned between ethyl

acetate and 1 N aqueous HCl. The separated organic phase

was washed with saturated brine, dried (MgSO₄), and then

concentrated in vacuo to obtain (()-3-[4-methoxy-3-(2-phen-

ylethoxy)phenyl]-2-pentylpropionic acid as a yellow oil (4.75

g, 99%), which was carried on to the next step: ¹H NMR

(CDCl₃) δ 0.85 (3 H, t, J ) 6.4 Hz, CH₃of Pen), 1.16-1.42 (6

H, m, 3 × CH₂), 1.46-1.59 (2 H, m, CH₂), 2.55-2.69 (2 H, m,

CH and one of CH₂of propionic acid), 2.85 (1 H, d d, J ) 4.9,

11.4 Hz, one of CH₂of propionic acid), 3.14 (2 H, t, J ) 7.6 Hz,

CH₂Ph), 3.83 (3 H, s, CH₃O), 4.19 (2 H, t, J ) 7.6 Hz, OCH₂-

Bn), 6.69 (1 H, d, J ) 1.8 Hz, ArH), 6.71 (1 H, dd, J ) 1.8, 8.6

Hz, ArH), 6.79 (1 H, d, J ) 8.6 Hz, ArH), 7.20-7.36 (5 H, m,

ArH); MS (CI) m/z 370 (M⁺), 105 (100%).

Exp er im en ta l Section

Ch em istr y. Melting points were determined on a Yanaco

MP-500D melting point apparatus and are uncorrected. In-

frared (IR) spectra were obtained on a Perkin-Elmer 1760

spectrometer. Proton nuclear magnetic resonance (NMR)

spectra were obtained using a Varian VXR-200 spectrometer.

Chemical shifts are reported in parts per million relative to

tetramethylsilane as an internal standard. Mass spectra (MS)

were obtained on a Simazu/Kratos HV-300. Elemental analy-

ses were performed by a Perkin-Elmer 240C (for carbon,

hydrogen, and nitrogen) or Yokokawa-denki IC7000P (for

halogen) and are within 0.4% of theory. Analytical thin-layer

chromatography was conducted on precoated silica gel 60 F254

plates (Merck). Chromatography was performed on silica gel

C-200, 100-200 mesh (Wako Pure Chemical) using the solvent

systems (volume ratios) indicated below. Each of the experi-

ments below illustrates one of the methods indicated in Table

Meth od A: (()-N-ter t-Bu toxyca r bon yl-1-p en tyl-2-[4-

m eth oxy-3-(2-ph en yleth oxy)ph en yl]eth ylam in e ((()-10e).

A triethyl phosphonoacetate (4.75 g, 21.2 mmol) was added

dropwise to a stirred suspension of 60% NaH in oil (0.86 g,

21.5 mmol) in 1,2-dimethoxyethane (25 mL) over 10 min. After

stirring for 1 h at room temperature, to the reaction mixture

was added n-pentyl bromide (3.23 g, 21.4 mL), and the

resulting mixture was heated at reflux for 3 h. To the cooling

mixture was added 60% NaH in oil (0.86 g, 21.5 mmol), and

the resulting suspension was stirred for 0.5 h at room

temperature. To the reaction mixture was added a solution of

4-methoxy-3-(2-phenylethoxy)benzaldehyde (9) (5.15 g, 20.1

mmol) in DME (10 mL), and the resulting mixture was allowed

to heat at reflux for 2 h. The mixture was then partitioned

between ethyl acetate and water. The separated organic phase

was washed with water, saturated aqueous NaHCO₃, and

A solution of (()-3-[4-methoxy-3-(2-phenylethoxy)phenyl]-

2-pentylpropionic acid (4.01 g, 10.8 mmol), triethylamine (3.32

g, 11.7 mmol), and diphenyl phosphorazidate (3.32 g, 11.8

mmol) in benzene (40 mL) was heated at reflux for 2 h. The

reaction mixture was concentrated in vacuo. The residue was

dissolved in tert-butyl alcohol (20 mL), and the resulting

solution was heated at reflux for 20 h. The concentrated

reaction mixture was dissolved in ethyl acetate, washed with

0.5 N aqueous sodium hydroxide, 5% aqueous KHSO₄, satu-

rated aqueous NaHCO₃, and saturated brine, dried (MgSO₄),

and then concentrated in vacuo. The residue was chromato-

graphed (hexanes/AcOEt, 25:1) and recrystallized from hex-

anes to obtain (()-10e as a colorless crystal (3.08 g, 64%): mp

91.5-92.5 °C; ¹H NMR (CDCl₃) δ 0.85 (3 H, t, J ) 6.5 Hz,

CH₃of Pen), 1.24-1.43 (8 H, m, 4 × CH₂), 1.38 (9 H, s, 3 ×

CH₃of t-Bu), 2.65 (2 H, d, J ) 6.6 Hz, CH₂of ethylamine),

3.16 (2 H, t, J ) 7.6 Hz, CH₂Ph), 3.65-3.89 (1 H, m, CH), 3.84

(3 H, s, CH₃O), 4.23 (1 H, br s, NH), 4.19 (2 H, t, J ) 7.6 Hz,

OCH₂Bn), 6.81-6.72 (2 H, m, ArH), 6.81 (1H, d, J ) 8.7 Hz,

ArH), 7.23-7.32 (5 H, m, ArH); MS (EI) m/z 441 (M⁺), 100

(100%); IR (KBr) 3357, 1687, 1591, 1530, 1445, 1427 cm^-1

Anal. (C₂₇H₃₉NO₄) C, H, N.

Meth od B: (()-1-P en tyl-2-[4-m eth oxy-3-(2-p h en yleth -

oxy)p h en yl]eth yla m in e Hyd r och lor id e ((()-5e). A solu-

tion of (()-10e (2.89 g, 6.54 mmol) in a mixture of trifluoro-

acetic acid (10 mL) and dichloromethane (10 mL) was stirred

at room temperature for 1.5 h. The reaction mixture was

Synthesis and SAR of 1-Alkyl-2-phenylethylamines

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3969

concentrated in vacuo, and the residue was dissolved in

dichloromethane (10 mL). To the resulting solution was added

4 N HCl in dioxane (10 mL, 40.0 mmol), concentrated, and

recrystallized from diisopropyl ether to obtain (()-5e as a

yellow crystal (1.88 g, 76%): mp 120.5-122 °C; ¹H NMR

(CDCl₃) δ 0.79 (3 H, t, J ) 6.2 Hz, CH₃of Pen), 1.10-1.70 (8

H, m, 4 × CH₂), 2.78 (1 H, d d, J ) 9.5, 13.4 Hz, one of CH₂-

Ar), 3.10-3.21 (3 H, m, CH₂Ph and one of CH₂Ar), 3.25-3.4

(1 H, m, CHN), 3.81 (3 H, s, CH₃O), 4.19 (2 H, t, J ) 7.5 Hz,

OCH₂Bn), 6.70-6.82 (3 H, m, ArH), 7.19-7.31 (5 H, m, ArH),

8.46 (3 H, br s, NH₃⁺); MS (CI) m/z 342 (M⁺+ 1, 100%), 325,

242, 105, 100; IR (KBr) 3436, 1603, 1517, 1467, 1455, 1428

cm^-1. Anal. (C₂₂H₃₁NO₂‚HCl) C, H, N.

treated by method C, and the resulting HCl salt was recrystal-

lized from toluene-hexanes to obtain (-)-6i (16.20 g, 67%):

mp 99-100 °C; [R]_D) -21.7 (c ) 0.580, CHCl₃); ¹H NMR

(CDCl₃) δ 0.80 (3 H, t, J ) 6.1 Hz, CH₃of iso-Pen), 0.83 (3 H,

t, J ) 6.1 Hz, CH₃of iso-Pen), 0.91 (3 H, t, J ) 7.4 Hz, CH₃of

Pr), 1.05-2.05 (7 H, m, 3 × CH₂and CHMe₂), 2.60-2.95 (2 H,

m, CH₂N), 2.91 (1 H, d d, J ) 8.2, 13.3 Hz, one of CH₂Ar),

3.16 (2 H, t, J ) 7.4 Hz, CH₂Ph), 3.10-3.35 (1 H, m, CHN),

3.34 (1 H, d d, J ) 5.4, 13.3 Hz, one of CH₂Ar), 3.84 (3 H, s,

CH₃O), 4.20 (2 H, t, J ) 7.4 Hz, OCH₂Bn), 6.70-6.90 (3 H, m,

ArH), 7.15-7.45 (5 H, m, ArH), 9.43 (2 H, br s, NH₂⁺); MS

(CI) m/z 384 (M⁺+ 1), 142 (100%); IR (KBr) 3447, 2956, 2793,

2511, 2428, 1592, 1520, 1497, 1454 cm^-1. Anal. (C₂₅H₃₇NO₂‚

HCl) C, H, N.

Meth od C: (()-N-P r op yl-1-p en tyl-2-[4-m eth oxy-3-(2-

p h en yleth oxy)p h en yl]eth yla m in e Hyd r och lor id e ((()-

6e) a n d (()-N,N-Dip r op yl-1-p en t yl-2-[4-m et h oxy-3-(2-

p h en yleth oxy)p h en yl]eth yla m in e Hyd r och lor id e ((()-

7e). A suspension of (()-5e (1.46 g, 3.86 mmol), propyl bromide

(0.72 g, 5.83 mmol), and K₂CO₃(1.34 g, 9.68 mmol) in N,N-

dimethylformamide (3.0 mL) was stirred at room temperature

for 5 days. The reaction mixture was partitioned between ethyl

acetate and water. The separated organic phase was washed

with water and saturated brine, dried (MgSO₄), concentrated

in vacuo, and then chromatographed (CHCl₃/EtOH, 200:1-

50:1) to separate the two desired products. Each product was

treated with 4 N HCl in dioxane in chloroform and gave (()-

6e (0.49 g, 30%, after recrystallization from toluene-hexanes)

as a colorless crystal and (()-7e (0.17 g, 10%) as a light yellow

amorphous solid.

The combined filtrates when resoluted were concentrated

and partitioned between diethyl ether and 1 N aqueous NaOH.

The separated organic phase was washed with 1 N aqueous

NaOH and saturated brine, dried (MgSO₄), and concentrated

in vacuo. The residue was treated with (S)-(+)-mandelic acid

(37% yield), and the resulting optical amine was reacted with

propyl bromide (73% yield), by the same procedure as for the

preparation of compound (-)-6i, to obtain (+)-6i: mp 98-99

°C; [R]_D) +21.9 (c ) 0.456, CHCl₃); H NMR (CDCl₃) δ 0.80

(3 H, t, J ) 6.1 Hz, CH₃of iso-Pen), 0.83 (3 H, t, J ) 6.1 Hz,

CH₃of iso-Pen), 0.91 (3 H, t, J ) 7.4 Hz, CH₃of Pr), 1.05-

2.05 (7 H, m, 3 × CH₂and CHMe₂), 2.60-2.95 (2 H, m, CH₂N),

2.91 (1 H, dd, J ) 8.2, 13.3 Hz, one of CH₂Ar), 3.16 (2 H, t, J

) 7.4 Hz, CH₂Ph), 3.10-3.35 (1 H, m, CHN), 3.34 (1 H, dd, J

) 5.4, 13.3 Hz, one of CH₂Ar), 3.84 (3 H, s, CH₃O), 4.20 (2 H,

t, J ) 7.4 Hz, OCH₂Bn), 6.70-6.90 (3 H, m, ArH), 7.15-7.45

(()-6e: mp 93-94 °C; H NMR (CDCl₃) δ 0.80 (3 H, t, J )

(5 H, m, ArH), 9.43 (2 H, br s, NH₂⁺); MS (CI) m/z 384 (M⁺

6.5 Hz, CH₃of Pen), 0.91 (3 H, t, J ) 7.4 Hz, CH₃of Pr), 1.10-

2.00 (10 H, m, 5 × CH₂), 2.65-2.90 (2 H, m, CH₂N), 2.90 (1 H,

dd, J ) 8.4, 13.2 Hz, one of CH₂Ar), 3.15 (2 H, t, J ) 7.5 Hz,

CH₂Ph), 3.10-3.30 (1 H, m, CHN), 3.34 (1 H, dd, J ) 5.0, 13.2

Hz, one of CH₂Ar), 3.84 (3 H, s, CH₃O), 4.20 (2 H, t, J ) 7.5

Hz, OCH₂Bn), 6.75-6.84 (3 H, m, ArH), 7.20-7.35 (5 H, m,

ArH), 9.44 (2 H, br s, NH₂⁺); MS (CI) m/z 384 (M⁺+ 1, 100%),

142; IR (KBr) 3436, 2955, 2857, 2796, 2741, 2515, 2428, 1605,

1589, 1519, 1498, 1455 cm^-1. Anal. (C₂₅H₃₇NO₂‚HCl) C, H, N.

1), 142 (100%); IR (KBr) 3523, 2955, 2795, 2511, 2427, 1592,

1520, 1498, 1454 cm^-1. Anal. (C₂₅H₃₇NO₂‚HCl) C, H, N.

Meth od E: 1,1-Dip r op yl-2-[4-m eth oxy-3-(2-p h en yleth -

oxy)ph en yl]eth ylam in e Fu m ar ate (8). A solution of 4-meth-

oxy-3-(2-phenylethoxy)phenylacetonitrile (11) (10.00 g, 37.4

mmol) in dried diethyl ether (50 mL) was added dropwise over

0.5 h to a refluxed solution of allylmagnesium bromide in dried

diethyl ether which was prepared by treatment of allyl bromide

(9.29 g, 76.8 mmol) and magnesium (1.93 g, 79.4 mmol) in

dried diethyl ether (100 mL). After heating for 8 h, the re-

sulting mixture was quenched with saturated aqueous NH₄Cl

and then extracted with ethyl acetate. The extract was washed

with saturated aqueous NH₄Cl and saturated brine, dried

(MgSO₄), concentrated in vacuo, and then chromatographed

(CHCl₃/EtOH, 100:1), followed by treatment with fumaric acid

in a mixture of acetone and diethyl ether to obtain 1,1-diallyl-

2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine fumarate

(2.03 g, 11%): mp 127-128.5 °C; ¹H NMR (DMSO-d₆) δ 2.10-

2.30 (4 H, m, 2 × CCH₂C of allyl), 2.69 (2 H, s, CH₂Ar), 3.03

(2 H, t, J ) 7.1 Hz, CH₂Ph), 3.73 (3 H, s, CH₃O), 4.13 (2 H, t,

J ) 7.1 Hz, OCH₂Bn), 5.11 (2 H, dd, J ) 5.11, 8.9 Hz, 2 × one

of CH₂dC), 5.18 (2 H, s, 2 × one of CH₂dC), 5.80-6.05 (2 H,

m, CHdC), 6.48 (2 H, s, CHdCH of fumaric acid), 6.76 (1H,

dd, J ) 1.5, 8.3 Hz, ArH at 6), 6.90 (1 H, d, J ) 8.3 Hz, ArH

at 5), 6.92 (1 H, d, J ) 1.5 Hz, ArH at 2), 7.15-7.40 (5 H, m,

ArH of Ph); MS (CI) m/z 352 (M⁺+ 1), 110 (100%); IR (KBr)

(()-7e: H NMR (CDCl₃) δ 0.78 (3 H, t, J ) 6.3 Hz, CH₃of

Pen), 0.92 (3 H, t, J ) 7.3 Hz, CH₃of Pr), 0.98 (3 H, t, J ) 7.3

Hz, CH₃of Pr), 1.05-2.15 (12 H, m, 6 × CH₂), 2.65-3.05 (5 H,

m, 2 × CH₂N and CHN), 3.16 (2 H, t, J ) 7.4 Hz, CH₂Ph),

3.40-3.55 (2 H, m, CH₂Ar), 3.84 (3 H, s, CH₃O), 4.22 (2 H, t,

J ) 7.4 Hz, OCH₂Bn), 6.80-6.90 (3 H, m, ArH), 7.20-7.40 (5

H, m, ArH), 11.83 (1 H, br s, NH⁺); MS (CI) m/z 426 (M⁺+ 1),

184 (100%); IR (KBr) 3401, 2934, 2874, 2607, 2471, 1661, 1605,

1591, 1516, 1455 cm^-1. Anal. (C₂₈H₄₃NO₂‚HCl) C, H, N.

Meth od D: (-)-N-P r op yl-1-(3-m eth ylbu tyl)-2-[4-m eth -

oxy-3-(2-p h en ylet h oxy)p h en yl]et h yla m in e Hyd r och lo-

r id e ((-)-6i) a n d (+)-N-P r op yl-1-(3-m et h ylb u t yl)-2-[4-

m eth oxy-3-(2-p h en yleth oxy)p h en yl]eth yla m in e Hyd r o-

ch lor id e ((+)-6i). After reaction of (()-N-tert-butoxycarbonyl-

1-(3-methylbutyl)-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethyl-

amine ((()-10i) (89.69 g, 203 mmol) in a mixture of trifluoro-

acetic acid (156 mL) and dichloromethane (156 mL) (method

B), to the concentrated residue was added saturated aqueous

NaHCO₃, followed by extraction with CH₂Cl₂. The extract was

dried (MgSO₄), concentrated in vacuo, and chromatographed

(CHCl₃/MeOH, 30:1-20:1) to obtain (()-1-(3-methylbutyl)-2-

[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (free amine

of (()-5i) (59.65 g, 86%).

A mixture of the free amine of (()-5i (59.65 g, 175 mmol)

and (R)-(-)-mandelic acid (26.58 g, 175 mmol) in 2-propanol

(257 mL) was heated at reflux to dissolve and left to stand

overnight. The precipitated crystal was collected by filtration,

and the recrystallization of the crystal from 2-propanol was

repeated four times to obtain mandelate (30.27 g). The

resulting crystal was partitioned between diethyl ether and 1

N aqueous NaOH. The separated organic phase was washed

with 1 N aqueous NaOH and saturated brine, dried (MgSO₄),

and concentrated in vacuo to obtain optical 5i (21.22 g, 36%).

3078, 2910, 1694, 1642, 1566, 1520, 1442, 1368, 1264 cm^-1

Anal. (C₂₃H₂₉NO₂‚C₄H₄O₄) C, H, N.

The fumarate (1.64 g, mmol) was treated with 2 N aqueous

NaOH in ethyl acetate to obtain the free amine. The free amine

was stirred with PtO₂(25 mg) in ethyl acetate (15 mL) under

an atmosphere of hydrogen. After the theoretical amount of

hydrogen was taken up, the suspension was filtered through

Celite. The filtrate was concentrated in vacuo and the chro-

matographed (CHCl₃/EtOH, 15:1), followed by treatment with

fumaric acid in a mixture of acetone and diethyl ether to give

8 (1.35 g, 82%): mp 167.5-168.5 °C; H NMR (DMSO-d₆) δ

0.85 (6 H, t, J ) 6.1 Hz, 2 × CH₃of Pr), 1.10-1.55 (8 H, m,

CH₂CH₂of Pr), 2.75 (2 H, s, CH₂Ar), 3.03 (2 H, t, J ) 7.0 Hz,

CH₂Ph), 3.73 (3 H, s, CH₃O), 4.14 (2 H, t, J ) 7.0 Hz, OCH₂-

Bn), 6.44 (2 H, s, CHdCH of fumaric acid), 6.73 (1 H, dd, J )

1.6, 8.1 Hz, ArH), 6.91 (1 H, d, J ) 8.1 Hz, ArH), 6.92 (1 H, d,

J ) 1.6 Hz, ArH), 7.15-7.40 (5 H, m, ArH); MS (CI) m/z 356

A mixture of the optical amine (19.53 g, 57.2 mmol), propyl

bromide (7.74 g, 62.9 mM), and K₂CO₃(9.49 g, 68.7 mmol) was

3970 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19

Nakazato et al.

(M⁺+ 1), 114 (100%); IR (KBr) 2962, 2870, 1692, 1650, 1520,

1454, 1444, 1380, 1264 cm^-1. Anal. (C₂₃H₃₃NO₂‚C₄H₄O₄) C, H,

(7) Danso-Danquah, R.; Bai, X.; Zhang, X.; Mascarella, S. W.;

Williams, W.; Sine, B.; Bowen, W. D.; Carroll, F. I. Synthesis

and σ Binding Properties of 1′- and 3′-Halo- and 1′,3′-Dihalo-N-

normetazocine Analogues. J . Med. Chem. 1995, 38, 2986-2989.

(8) Hanner, M.; Moebius, F. F.; Flandorfer, A.; Knaus, H. G.;

Striessing, J .; Kempner, E.; Glossmann, H. Purification, molec-

ular cloning, and expression of the mammalian sigma 1-binding

site. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 8072-8077.

(9) Seth, P.; Fei, Y. J .; Li, H. W.; Huang, W.; Leibach, F. H.; Gana-

pathy, V. Cloning and functional characterization of a sigma

receptor from rat brain. J . Neurochem. 1998, 70, 922-931.

(10) Lehmann, J . Sigma receptor, schizophrenia and cytochrome

P-450. Drug News Perspect. 1991, 4, 208-210.

σ, σ₁, σ₂, a n d Dop a m in e D₂Bin d in g Assa ys. Compounds

5-8 were examined for affinity at σ sites labeled with [³H]-

(+)-3-(3-hydroxphenyl)-N-(1-propyl)piperidine (3-PPP) using

guinea pig brain membranes, at σ₁sites labeled with [³H]-(+)-

N-isopetenylnormetazocine (pentazocine) using guinea pig

brain membranes, at σ₂sites labeled with [³H]-1,3-di-o-

tolylguanidine (DTG) in the presence of 100 nM (+)-pentazo-

cine using guinea pig brain membranes, and at dopamine D₂

receptors labeled with [³H]-(-)-N-[(1-ethylpyrrolidin-2-yl)m-

ethyl]-3,5-dichloro-2-hydroxy-6-methoxybenzamide¹⁹(raclo-

pride) using rat striatal membranes (Table 2), using the

procedures described in the literature.^12,19

(11) Abou-Gharbia, M.; Ablordeppey, Y. S.; Glennon, A. R. Sigma

Receptors and their Ligands: The Sigma Enigma. Annu. Rep.

Med. Chem. 1993, 28, 1-9.

(12) Chaki, S.; Tanaka, M.; Muramatsu, M.; Otomo, S. NE-100, a

novel potent σ ligand, preferentially binds to σ1 binding sites.

Eur. J . Pharmacol. 1994, 251, R1-R2.

(13) The procedure for preparation of [³H]-compound 1 has not been

presented. This labeled compound was prepared by treatment

of N,N-dipropyl-2-[4-hydroxy-3-(2-phenylethoxy)phenyl]ethyl-

amine, a compound shown in ref 16, with [³H]methyl iodide in

N,N-dimethylformamide containing potasium carbonate in an

Amersham laboratory.

Refer en ces

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pheochromocytoma (PC12) cells: Decreased affinity for (+)-

benzomorphans and lower molecular weight suggest a different

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1990, 523, 244-253.

(2) Berardi, F.; Santoro, S.; Perrone, R.; Tortorella, V.; Govoni, S.;

Lucchi, L. N-[omega-Tetralin-1-yl)alkyl] derivatives of 3,3-

dimethylpiperidine are highly potent and selective sigma1 or

sigma2 ligands. J . Med. Chem. 1998, 41, 3940-3947.

(3) J ohn, C. S.; Lim, B. B.; Vilner, B. J .; Geyer, B. C.; Bowen, W. D.

Substituted halogenated arylsulfonamides: a new class of sigma

receptor binding tumor imaging agents. J . Med. Chem. 1998,

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(4) Huang, Y.; Hammond, P. S.; Whirrett, B. R.; Kuhner, R. J .; Wu,

L.; Childer, S. R.; Mach, R. H. Synthesis and quantitative

structure-activity relationships of N-(1-benzylpiperidin-4-yl)-

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tive sigma1 receptor ligands. J . Med. Chem. 1998, 41, 2361-

2370.

(14) Yamamoto, H.; Miura, R.; Yamamoto, T.; Shinohara, K.; Wa-

tanabe, M.; Okuyama, S.; Nakazato, A.; Nukada, T. Amino acid

residues in the transmembrane domain of type 1 sigma receptor

critical for ligand binding. FEBS Lett. 1999, 445, 19-22.

(15) Okuyama, S.; Chaki, S.; Yae, T.; Nakazato, A.; Muramatsu, M.

Autoradiographic characterization of binding sites for [³H]NE-

100 in guinea pig brain. Life Sci. 1995, 57, PL333-337.

(16) Nakazato, A.; Ohta, K.; Sekiguchi, Y.; Okuyama, S.; Chaki, S.;

Kawashima, Y.; Hatayama, K. Design, Synthesis, Structure-

Activity Relationships, and Biological Characterization of Novel

Arylalkoxyphenylalkylamine σ Ligands as Potential Antipsy-

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(5) Ronsisvalle, G.; Marrazzo, A.; Prezzavento, O.; Pasquinucci, L.;

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rivatives. Novel and selective sigma ligands with antagonist

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(18) Shioiri, T.; Ninomiya, K.; Yamada, S. Diphenylphosphoryl Azide.

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J M990135J

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