The 14-alkyl- and 14-alkenyl-5β-methylindolomorphinan series provide δ-selective partial opioid agonists

Article abstract of DOI:10.1002/hlca.200390080

A series of 14β-alkyl- and 14β-alkenyl-5β-methylindolomorphinans was synthesized and evaluated in opioid binding and functional assays. While being relatively nonselective in binding assays, the 14-cinnamyl and 14-isopentyl members showed selective opioid

Full text of DOI:10.1002/hlca.200390080

Helvetica Chimica Acta Vol. 86 (2003)
793
The 14-Alkyl- and 14-Alkenyl-5b-methylindolomorphinan Series Provide
d-Selective Partial Opioid Agonists
by Peter Grundta), Fernando Martinez-Bermejob), John W. Lewisa), Stephen M. Husbands*a)
a) Department of Pharmacy and Pharmacology, University of Bath, Bath BA27AY, UK
b) School of Chemistry, University of Bristol, Bristol, BS81TS, UK
A series of 14b-alkyl- and 14b-alkenyl-5b-methylindolomorphinans was synthesized and evaluated in
opioid binding and functional assays. While being relatively nonselective in binding assays, the 14-cinnamyl and
14-isopentyl members showed selective opioid d-receptor partial agonist activity in [35S]GTPgSassays.
Introduction. The d-opioid receptor (DOR) is one of three types of opioid
receptors. Agonists for this receptor have analgesic properties but have much lower
propensity than traditional m-opiates, e.g., morphine, to induce physical dependence
and to be abused [1][2]; they also have immunostimulant properties [3][4]. The
indolomorphinan structure (e.g., 1 and 2) is a major source of selective DOR ligands;
the 17-(cyclopropylmethyl) (CPM) derivatives (e.g., naltrindole (NTI; 1a)) generally
are d-selective antagonists, and the 17-methyl derivatives (e.g., oxymorphindole (OMI;
2a)) are d-agonists or partial agonists [5].
Ethylation of the 14-hydroxy group of NTI to give 1b reduced d-affinity but not d-
selectivity, whereas introduction of a 5b-methyl group (as in 1c) had little effect on d-
affinity but reduced m- and k-affinity so that d-selectivity was substantially increased
[6]. In our search for ligands selective for DOR, particularly d-agonists related to OMI,
we have investigated 14-substituted indolomorphinans [7], and, herein, we report the
extension of our studies to a series of 14b-alkyl- and 14b-alkenylindolomorphinans,
only one example of which (6f) has previously been reported [8].

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Chemistry. The 7,8-dihydro-14b-(3-phenylpropyl)codeinone (4a) was prepared by
hydrogenation of 14b-cinnamylcodeinone (3) [9] and converted to 6a by Fischer
indolization ( ! 5a) followed by 3-O-demethylation with BBr3 (Scheme). The 14b-
alkenyl-7,8-dihydro-5b-methylcodeinones 4c and 4d [10] were similarly converted to
the indole derivatives 5c and 5d, respectively, which, with sodium propanethiolate, gave
the target indolomorphinans 6c and 6d, respectively; these were hydrogenated to give
the corresponding alkyl analogues 6b and 6e (Scheme).
Scheme
i) PhNHNH2, AcOH, HCl. ii) PrSNa, HMPA or BBr3, CH2Cl2, MeOH.
Results and Discussion. Receptor binding affinities for the test compounds were
determined in recombinant human opioid receptors (HOR) transfected into chinese
hamster ovary (CHO) cells [11]. The displaced type-selective opioid radioligands were
[3H]Cl-DPDPE (d), [3H]U69,593 (k), and [3H]DAMGO (m). In these assays (Table 1),
the new ligands 6a e have moderate to high d-affinity but little d-selectivity. The
exception is 6e, which has 30-fold selectivity for d as a result of its very low k- and m-
affinity. Comparison of 6a with its 5-methyl congener 6b shows that the latter has
fivefold lower m-affinity but higher d-affinity, with the result that modest m-selectivity in
6a is transformed into similar d-selectivity in the 5-methyl analogue. Comparison of the
previously reported 6f [8] with 6e shows that, in this case, the 5-methyl group is
primarily associated with a ninefold loss of d-affinity giving lower d-selectivity. Since
the published data for 6f refers to different assay conditions, the comparison with 6e is
only approximate. It is interesting that in the 5-methyl series, insertion of an O-atom as
the linkage to C(14) as in 2d and 2e [12], when compared to 6b and 6e, has very little
effect on d-affinity. This suggests that the O-atom in the alkoxy derivatives 2 is unlikely
to be involved in binding to the DOR as a H-bond acceptor. Introduction of
unsaturation into the side-chain of the indolomorphinans, as in 6c and 6d (cf. 6b and 6e)
has very little effect on opioid receptor binding affinity (Table 1).
The opioid receptor functional activity of the new ligands was determined in assays
involving stimulation of [35S]GTPgSin recombinant human opioid receptors trans-
fected into CHO cells [11][13]. In addition to potency values (EC50), maximum

Helvetica Chimica Acta Vol. 86 (2003)
795
Table 1. Binding of 14-Alkyl- and 14-Alkenylindolomorphinans to Recombinant HOR9
Ki [nm]
k/d
m/d
d
k
m
6a
6b
6c
6d
6e
6f a)
23.6 Æ 2.6
9.6 Æ 2.3
12.5 Æ 2.5
51.4 Æ 2.7
13.1 Æ 1.0
1.4
63.3 Æ 16.4
4.91 Æ 0.47
2.7
0.21
2.5
3.5
4.9
32
133
36.4 Æ 0.16
94.2 Æ 0.49
440 Æ 119
457 Æ 110
204
24.3 Æ 6.9
43.8 Æ 1.6
254 Æ 4.9
422 Æ 83.5
186
4.0
7.5
8.6
35
146
a) Data from [8].
efficacy was determined as % of the effect of standard agonists, DPDPE (d), U69593
(k), and DAMGO (m) (Table 2). In these assays, the indolomorphinans are moderately
potent d-partial agonists with varying levels of selectivity for d over m. Though
introduction of unsaturation into the side chain of 6b results in some loss of d-potency,
there is a higher loss of k- and particularly m-potency (180-fold) so that 6c is an opioid
partial agonist with d-potency 94-times higher than k- and 37-times higher than m-
potency. The 14-isopentyl ligand 6e has even higher selectivity as a d-partial agonist
(147-fold over k, 53-fold over m) but its efficacy for all three opioid receptor types is
substantially lower than that of 6c. These d-selectivity values in the functional assays
are substantially higher than those recorded in the binding assays. Such discrepancies
are not unusual in series of selective opioid ligands [14]. In the current series, the main
reason is lower than expected k- and m-agonist potencies. The effect of introducing side-
chain unsaturation into 6e, to give 6d, is to reduce d-potency to a greater extent than m-
and k-potency resulting in only modest d-selectivity.
Table 2. Stimulation of [35S]GTPgS Binding in Recombinant HOR9
d
k
m
EC50 [nm]
% stim
EC50 [nm]
% stim
EC50 [nm]
% stim
6a
6b
6c
6d
6e
7.53 Æ 0.58
4.02 Æ 0.32
21.8 Æ 5.3
90.1 Æ 30
65
59
79
43
45
96.5 Æ 0.9
175 Æ 9.2
67
33
60
31
20
21.5 Æ 7.7
4.46 Æ 0.98
804 Æ 41
91
83
85
72
28
2046 Æ 60
945 Æ 191
1936 Æ 488
1201 Æ 92
703 Æ 150
13.2 Æ 1.7
In summary, new 5b-methylindolomorphinan ligands substituted at C(14) with
phenylpropyl, cinnamyl, or isopentenyl groups (see 6a d) were shown to have
moderate affinity for DOR. The 5b-methyl-14-isopentyl derivative 6e was the only
ligand to show appreciable d-selectivity in opioid receptor binding assays, but both 6e
and the 14-cinnamyl analogue 6c were substantially selective as d-partial agonists in the
[35S]GTPgSassay.
This work was funded by NIDA Grants DA 07315 and DA 00254 and pharmacological data provided by
NIDA/OTDP.

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Helvetica Chimica Acta Vol. 86 (2003)
Experimental Part
General. M.p.: Gallenkamp MFB-595 melting-point apparatus; uncorrected. IR Spectra: Perkin-Elmer 881
instrument; in cmÀ1. NMR Spectra: Jeol Lambda-300-MHz instrument: 1H at 300 MHz, 13C at 75 MHz; d in ppm
with SiMe4 as a standard. High- and low-resolution MS: V.G.-Autospec instrument equipped with a Fisons
autosampler; EI at 70 eV; m/z (rel.%). Microanalysis: Perkin-Elmer 240C analyzer.
4,5a-Epoxy-3-methoxy-17-methyl-14b-(3-phenylpropyl)morphinan-6-one (4a). A mixture of 3 (0.46 g,
1.11 mmol) and anh. K2CO3 (0.29 g, 2.10 mmol) in AcOH (10 ml) and EtOH (1 ml) was added to a slurry of
10% Pd/C (0.29 g) and hydrogenated at 30 psi for 4 h at r.t. The mixture was then filtered through Celite and
washed with CH2Cl2 and the solvents were evaporated. H2O/Ammonia was added to the solid, and the free base
was extracted with CH2Cl2. The extract was washed with brine, dried (MgSO4), and evaporated. Trituration with
EtOH yielded 4a (0.36 g, 78%). White foam. Rf (MeOH/CH2Cl2 10 :90) 0.66. IR (CHCl3): 1722s (CˆO).
1H-NMR (CDCl3); 2.31 (s, MeN); 3.07 (d, J ˆ 18.5, HbÀC(10)); 3.87 (s, MeOÀC(3)); 4.45 (s, HÀC(5)); 6.62
(d, J ˆ 8.3, HÀC(1)); 6.68 (d, J ˆ 8.3, HÀC(2)); 7.25 (m, Ph). 13C-NMR (CDCl3): 20.0; 25.2; 25.6; 28.8; 29.3;
36.3; 36.4; 39.1; 43.2; 46.0; 49.2; 56.7; 59.3; 89.7; 114.1; 119.4; 125.9; 126.5; 128.3; 128.5; 130.1; 142.3; 142.7; 144.8;
‡
‡
208.9. EI-MS: 417 (100, M ). HR-MS: 417.2301 (C27H31N1O3 ; calc. 417.2303).
6,7-Didehydro-4,5a-epoxy-3-methoxy-17-metyl-14b-(3-phenylpropyl)-indolo[2',3':6,7]morphinan (5a). A
soln. of 4a (0.1 g, 0.24 mmol) and phenylhydrazine hydrochloride (0.05 g, 0.33 mmol) in conc. HCl soln./AcOH
1:4 (20 ml) was stirred to reflux for 7 h. The mixture was then allowed to cool and poured into ice/ammonia. The
aq. layer was extracted with CH2Cl2 (3 Â 10 ml), the combined org. extract washed with brine, dried (NaSO4),
and evaporated, and the residue purified by column chromatography (CH2Cl2/CH3OH 98 :2): 5a (0.08 g, 73%).
Solid. Rf (CH2Cl2/CH3OH 95 :5) 0.48. IR (CHCl3): 3465. 1H-NMR (CDCl3, selected signals): 2.35 (s, MeN); 3.14
(d, J ˆ 18.5, HaÀC(10)); 3.72 (s, MeOÀC(3)); 5.60 (s, HÀC(5)); 6.60 (s, HÀC(1), HÀC(2)); 7.1 (m, 9 arom. H
(ind, Ph)); 8.30 (s, NH(ind)). 13C-NMR (CDCl3): 20.5; 24.1; 25.8; 29.9; 30.2; 36.3; 42.4; 43.4; 46.0; 46.9; 55.9;
60.0; 84.9; 111.2; 112.3; 113.0; 118.5; 118.8; 119.1; 122.5; 125.4; 126.9; 127.2; 128.1; 128.2; 128.4; 128.6; 129.7;
‡
‡
131.5; 136.9; 142.7; 143.0; 143.5. EI-MS: 490 (80, M ). HR-MS: 490.2610 (C33H34N2O2 ; calc. 490.2620).
6,7-Didehydro-4,5a-epoxy-17-methyl-14b-(3-phenylpropyl)indolo[2',3':6,7]morphinan-3-ol (6a). A 1m
BBr3 soln. in CH2Cl2 (1.2 ml, 1.12 mmol) was added dropwise to a soln. of 5a (85 mg, 0.17 mmol) in anh.
CH2Cl2 and the mixture was stirred at r.t. for 15 min. After that time, it was added carefully to MeOH at 08 and
refluxed in the open-mouthed flask for 30 min. The mixture was then quenched with ice/ammonia 1:1, stirred
for 30 min, and then extracted (3Â) with MeOH/CHCl3 1 :3. The extract was washed with brine, dried
(MgSO4), and evaporated and the residue purified by column chromatography. Further purification by prep.
TLC (MeOH/CH2Cl2 5 :95) yielded 6a (47 mg, 57%). Solid. Rf (CH2Cl2/MeOH 10 :90) 0.41. M.p. (hydro-
chloride) >2508. IR (CHCl3): 3467. 1H-NMR (CDCl3, selected signals): 2.33 (s, MeN); 5.55 (s, HÀC(5)); 6.56
(d, J ˆ 8.2, HÀC(1)); 6.65 (d, J ˆ 8.2, HÀC(2)); 7.1 (m, 9 arom. H (ind, Ph)); 8.48 (s, NH(ind)). 13C-NMR
(CDCl3): 20.8; 24.1; 25.9; 29.8; 30.1; 36.3; 42.7; 43.4; 46.1; 47.0; 60.1; 85.8; 111.4; 113.4; 116.7; 118.9; 119.3; 119.5;
‡
122.7; 125.6; 126.9; 128.2; 128.4; 129.1; 131.5; 137.0; 138.8; 142.0; 142.7. EI-MS: 476 (100, M ). HR-EI-MS.
‡
476.2463 (C32H32N2O2 ; calc. 476.2457). Anal. calc. for C32H32N2O2 ¥ 2 HCl ¥ 0.1 CH2Cl2: C 69.09, H 6.17, N 5.01;
found: C 69.41, H 6.26, N 4.61.
6,7-Didehydro-4,5a-epoxy-3-methoxy-5,17-dimethyl-14b-[(2E)-3-methylbut-2-enyl]indolo[2',3':6,7]mor-
phinan (5d). A soln. of 4d (0.63 g, 1.65 mmol) and phenylhydrazine hydrochloride (0.30 g, 2.1 mmol) in AcOH
(5 ml) was refluxed for 4 h. Then most of the solvent was evaporated, the residue basified (NH4OH) and
extracted with CHCl3 (3 Â 10 ml), the extract dried (MgSO4) and evaporated, and the crude product purified by
flash chromatography (CH2Cl2/CH3OH 30 :1 ! 20 :1): 5d (0.52 g, 69%). Foam. Rf (CH2Cl2/CH3OH 20 :1) 0.46.
IR (film): 3582s, 3406. 1H-NMR (CDCl3): 1.36 (s, 3 H); 1.47 (m, 1 H); 1.73 (s, 3 H); 1.90 (s, 3 H); 2.03 2.42
(m, 4 H); 2.36 (s, 3 H); 2.53 2.67 (m, 3 H); 2.87 3.14 (m, 3 H); 3.71 (s, 3 H); 5.23 (m, 1 H); 6.56 (s, 2 H); 7.00
(1 H); 7.12 (td, J ˆ 7.6, 1.2, 1 H); 7.27 (d, J ˆ 8.3, 1 H); 7.33 (d, J ˆ 7.9, 1 H); 8.18 (s, 1 H). 13C-NMR (CDCl3):
18.10; 20.55; 21.15; 23.95; 26.25; 27.27; 27.34; 43.33; 43.95; 46.02; 47.31; 55.76; 59.99; 89.98; 111.07; 111.71; 111.83;
118.25; 118.80; 119.07; 120.57; 122.38; 127.19; 127.45; 132.87; 133.63; 134.58; 136.66; 142.52; 143.10. EI-MS: 454
‡
‡
(100, M ). HR-EI-MS: 454.2626 (C30H34N2O2 ; calc. 454.2620).
6,7-Didehydro-4,5a-epoxy-3-methoxy-5,17-dimethyl-14b-[(2E)-3-phenylprop-2-enyl]indolo[2',3':6,7]mor-
phinan (5c). Prepared from 4c (0.28 g, 0.65 mmol) and phenylhydrazine hydrochloride (0.14 g, 1.0 mmol) as
1
described for 5d: 5c (0.13 g, 25%). Foam. Rf (CH2Cl2/CH3OH 20 :1) 0.48. IR (film): 3408. H-NMR (CDCl3):
1.51 (dd, J ˆ 2.2, 12.5, 1 H); 1.91 (s, 3 H); 2.15 2.32 (m, 3 H); 3.38 2.46 (m, 1 H); 2.41 (s, 3 H); 2.55 2.66
(m, 2 H); 2.78 (d, J ˆ 15.6, 1 H); 3.07 3.14 (m, 2 H); 3.28 (ddd, J ˆ 13.2, 5.4, 1.5, 1 H); 3.73 (s, 3 H); 6.29 6.28
(m, 2 H); 6.55 6.60 (m, 2 H); 7.05 (m, 1 H); 7.13 7.23 (m, 2 H); 7.27 7.34 (m, 5 H); 7.38 (d, J ˆ 7.8, 1 H); 8.18

Helvetica Chimica Acta Vol. 86 (2003)
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(s, 1 H). 13C-NMR (CDCl3): 20.59; 21.09; 23.96; 27.29; 32.60; 43.33; 43.78; 46.02; 47.31; 55.74; 60.25; 89.85;
111.16; 111.49; 111.73; 118.35; 118.8; 119.23; 122.59; 125.97; 126.96; 127.08; 127.13; 127.25; 128.53; 132.62;
‡
‡
133.48; 133.57; 136.63; 137.92; 142.57; 143.09. EI-MS: 502 (100, M ). HR-EI-MS: 502.2613 (C34H34N2O2 ; calc.
502.2620).
6,7-Didehydro-4,5a-epoxy-5,17-dimethyl-14b-[(2E)-3-methylbut-2-enyl]indolo[2',3':6,7]morphinan-3-ol
(6d). A sample of 5d (0.20 g, 0.44 mmol) and NaH (0.12 g, 3.0 mmol; 60%) were suspended in HMPA (1 ml),
and under N2, propane-1-thiol (0.32 ml, 3.5 mmol) was added. After the effervescence had subsided, the mixture
was heated at 1208 for 4 h. Then the mixture was diluted with sat. NH4Cl soln. (10 ml), and, after stirring
overnight, it was extracted with AcOEt (3 Â 10 ml). The combined extract was dried (MgSO4) and evaporated
and the residue purified by flash chromatography (gradient AcOEt/CH2Cl2): 6d (0.14 g, 72%). Solid. Rf
(AcOEt) 0.71. M.p. (oxalate) 193 1958. IR (film, oxalate): 3205. 1H-NMR (CDCl3, selected signals): 1.34
(s, 3 H); 1.72 (s, 3 H); 1.80 (s, 3 H); 2.35 (s, 3 H); 2.89 (dd, J ˆ 12.7, 6.1, 1 H); 2.97 3.18 (m, 2 H); 5.21 (m, 1 H);
6.49 (d, J ˆ 8.2, 1 H); 6.59 (d, J ˆ 7.9, 1 H); 6.96 (m, 1 H); 7.06 (m, 1 H); 7.20 (d, J ˆ 8.3, 1 H); 7.29 (d, J ˆ 7.6,
1 H); 8.55 (m, 1 H). 13C-NMR (CDCl3): 18.06; 20.73; 21.02; 23.97; 26.20; 27.20; 27.37; 43.28; 44.06; 46.07; 47.47;
60.08; 90.72; 111.11; 111.85; 116.39; 118.67; 118.77; 118.97; 120.62; 122.31; 126.92; 127.14; 132.86; 133.43; 134.45;
‡
136.81; 138.41; 142.01. EI-MS: 440 (100), 369 (39). HR-EI-MS: 440.2461 (C 29H32N2O2 ; calc. 440.2464). Anal.
calc. for C29H32N2O2 ¥ (COOH)2 ¥ 1.5 H2O: C 66.77, H 6.69, N 5.02; found: C 66.38, H 6.76, N 4.82.
6,7-Didehydro-4,5a-epoxy-5,17-dimethyl-14b-[(2E)-3-phenylprop-2-enyl]indolo[2',3':6,7]morphinan-3-ol
(6c). From 5c (0.28 g, 0.56 mmol) as described for 6d: 6c (0.21 g, 77%). Solid. M.p. >2308. Rf (AcOEt) 0.82. IR
1
(film): 3434. H-NMR (CDCl3): 1.48 (m, 1 H); 1.87 (s, 3 H); 2.09 2.34 (m, 3 H); 2.38 (m, 1 H); 2.40 (s, 3 H);
2.57 (dd, J ˆ 18.8, 6.1, 1 H); 2.63 (dd, J ˆ 11.2, 1 H); 2.75 (d, J ˆ 15.6, 1 H); 3.06 3.12 (m, 2 H); 3.24 (−d×, J ˆ
12.4, 1 H); 6.26 6.34 (m, 2 H); 6.54 (d, J ˆ 8.3, 1 H); 6.60 (d, J ˆ 8.3, 1 H); 7.02 (m, 1 H); 7.13 (m, 1 H); 7.18
7.35 (m, 7 H); 8.33 (s, 1 H). 13C-NMR (CDCl3): 20.72; 21.07; 23.91; 27.24; 32.53; 43.29; 43.93; 46.02; 47.48; 60.22;
91.10; 111.20; 111.76; 116.36; 118.86; 119.01; 119.26; 122.69; 125.99; 126.95; 126.99; 127.02; 127.18; 128.53;
‡
132.64; 133.02; 133.52; 136.67; 137.88; 138.01; 141.72. FAB-MS: 489 (100, [ M ‡ 1] ). Anal. calc. for C33H32N2O2 ¥
(COOH)2 ¥ C2H5OH: C 71.14, H 6.45, N 4.48; found: C 71.23, H 6.63, N 4.69.
6,7-Didehydro-4,5a-epoxy-5,17-dimethyl-14b-(3-methylbutyl)-indolo[2',3':6,7]morphinan-3-ol (6e). A sus-
pension of 6d (0.29 g, 0.66 mmol) and 10% Pd/C (0.13 g) in AcOEt (50 ml) was stirred under H2 for 24 h. The
catalyst was filtered off over Celite, and the crude mixture was purified by flash chromatography (silica gel,
AcOEt/CH2Cl2 gradient): 6e (0.24 g, 82%). Solid. M.p. 199 2018. Rf (AcOEt): 0.81. IR (film): 3381. 1H-NMR
(CDCl3): 0.72 (d, J ˆ 6.4, 3 H); 0.83 (d, J ˆ 6.3, 3 H); 1.17 (m, 1 H); 1.21 1.42 (m, 4 H); 1.81 (s, 3 H); 2.11 2.38
(m, 4 H); 2.33 (s, 3 H); 2.52 2.66 (m, 3 H); 3.02 3.09 (m, 2 H); 5.24 (s, 1 H); 6.51 (d, J ˆ 7.8, 1 H); 6.57 (d, J ˆ
8.3, 1 H); 6.99 (m, 1 H); 7.08 (td, J ˆ 7.6, 1.5, 1 H); 7.19 (d, J ˆ 8.3, 1 H); 7.34 (d, J ˆ 8.3, 1 H); 8.46 (s, 1 H).
13C-NMR (CDCl3): 20.71; 21.1; 22.76; 22.88; 23.77; 26.52; 27.13; 28.59; 32.9; 42.54; 43.32; 45.86; 47.63; 59.67;
91.20; 111.14; 111.95; 116.21; 118.78; 118.85; 119.03; 122.47; 127.08; 127.12; 133.00; 133.06; 136.67; 138.01; 141.64.
‡
EI-MS: 442 (100), 371 (42), 314 (31). HR-EI-MS: 442.2619 (C 29H34N2O2 ; calc. 442.2620). Anal. calc. for
C29H34N2O2 ¥ (COOH)2 ¥ 1.75H2O: C 66.24, H 6.72, N 4.98; found: C 66.12, H 6.93, N 4.83.
6,7-Didehydro-4,5a-epoxy-5,17-dimethyl-14b-(3-phenylpropyl)-indolo[2',3':6,7]morphinan-3-ol (6b). As
described for 6e, from 6c (0.21 g, 0.43 mmol) and 10% Pd/C (0.15 g) in AcOEt (50 ml): 6b (0.19 g, 90%).
Solid. M.p. 196 198. Rf (AcOEt): 0.80. IR (film): 3404. 1H-NMR (CDCl3): 1.32 (dd, J ˆ 12.5, 3.2, 1 H); 1.40
(m, 1 H); 1.55 (m, 1 H); 1.81 (s, 3 H); 2.34 (s, 3 H); 3.02 3.11 (m, 2 H); 6.52 (d, J ˆ 8.1, 1 H); 6.58 (d, J ˆ 8.1,
1 H); 7.01 (m, 1 H); 7.08 7.13 (m, 4 H); 7.17 7.22 (m, 3 H); 7.33 (d, J ˆ 7.7, 1 H); 8.38 (s, 1 H). 13C-NMR
(CDCl3): 20.73; 20.97; 23.99; 25.93; 27.07; 28.95; 36.43; 42.57; 43.33; 45.88; 47.51; 59.86; 91.02; 111.18; 111.77;
116.31; 118.82; 118.87; 119.08; 122.54; 125.53; 126.90; 126.99; 128.15; 128.23; 128.39; 132.85; 133.05; 136.63;
‡
‡
138.10; 141.70; 142.88. EI-MS: 490 (100, M ). HR-EI-MS: 490.2618 (C33H34N2O2 ; calc. 490.2620). Anal. calc.
for C33H34N2O2 ¥ (COOH)2 ¥ 2.25 H2O: C 67.67, H 6.57, N 4.51; found: C 67.53, H 6.16, N 4.41.
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Received October 23, 2002