Molecular structure of opiate alkaloids. Part 11. Crystal structures of 4-methylhomobenzomorphan hydrobromide (Ij

and 4,12 P-dimethylhomobenzomorphan (11)

ANDRB G. MICHEL' Laboratoire de chimie structurale, Universite' de Sherbrooke, Sherbrooke (QuP.), Canada JIK 2RI

GUY EVRARD AND BERNADETTE NORBERG Facultks Universitaires Notre-Dame de la Paix, rue de Bruxelles, 61, B5000 Namur, Belgium

AND

E U G ~ N E MILCHERT Politechnika Szcecinska, Szczecin, Poland, 0422141, PS PL

Received September 18, 1 9 8 7 ~

ANDRO G. MICHEL, GUY EVRARD, BERNADETTE NORBERG, and EUGBNE MILCHERT. Can. J . Chem. 66, 1763 (1988). The two title compounds belong to the family homobenzomorphans. Their analgesic properties are comparable to morphine

but without inducing physical dependence. This work presents the results of X-ray diffraction and NMR studies to elucidate the conformational properties particular to this class of compounds. More specifically, the spatial orientation of the nitrogen lone-pair are compared to those observed for other related molecules. The two molecules adopt the same L-shaped structure and the 16P-methyl substituent present in the second molecule does not modify this structure. Although very different in both structures, the intermolecular interactions do not alter the molecular conformation. The nitrogen lone pair is oriented away from the benzene ring and its orientation is conserved in solution, as proven by nrnr studies. The main conclusions are that the seven-membered ring shows very specific conformational properties and that the lone-pair orientation is predictable, according to the position of the nitrogen in the ring. Finally, it is concluded that correlations between the nitrogen lone-pair orientation and the analgesic activity have to be reconsidered.

ANDRO G. MICHEL, GUY EVRARD, BERNADETTE NORBERG et E U G ~ N E MILCHERT. Can. J. Chem. 66, 1763 (1988). Les deux composts faisant l'objet de cette Ctude, appartiennent i la famille des homobenzomorphanes. Leurs proprittts

analgtsiques se sont avtrtes trks inttressantes sous deux aspects: ils conservent une activitt proche de la morphine et d'autre part ne provoquent pas de dtpendance physique. Le prtsent travail vise i mettre en tvidence les proprittts conformatio~elles caracttristiques de ces composts, en vue d'en expliquer les proprittts typiques en terme de conformations. Plus particulikrement, I'orientation de la paire libre de I'azote est comparte 21 celle que l'on observe dans d'autres composCs analgksiques. I1 apparait que les deux moltcules adoptent la forme en L caracttristique et que le groupe 16P-mCthyl present dans le compost 11, n'induit aucune modification conformationnelle importante. Les interactions intermoltculaires sont tgalement dtcrites; quoique trks difftrentes d'une moltcule i I'autre, elles n'induisent pas non plus de modification conformationnelle notoire. Le comportement de ces moltcules en solution est aussi Ctudit. I1 s'avkre que ce type de moltcule posstdant un cycle C i 7 membres oriente la paire libre de l'azote de f a ~ o n sptcifique selon la position de l'atome d'azote dans le cycle. On doit tgalement conclure que la corrilation entre cette orientation et I'activitt analgtsique de ces moltcules doit &tre reconsidtrte.

Introduction The present work is part of a more general crystal and

molecular structure study of opiate alkaloids. The first part was published earlier (1) and reported oripavine and thebaine structure determinations in order to analyse the geometrical properties of narcotic opioids; the influence of the 16P-aryl substitution adjacent to the N atom in the piperidinyl ring was also discussed.

The present paper deals with opiate alkaloids where the classical C ring has been changed for a seven-membered ring with the N atom at the second position. These compounds have been found to be very active as opioids: analgesic activity of title compounds were determined using optically resolved stereoisomers (2, 3). Surprisingly, it was reported that the optical resolution gave no effect on the analgesic activity of compound I. Nevertheless, the levo isomer of compound I1 was analgesically much more potent than the dextro isomer and equipotent with morphine (3).

In light of X-ray structure determination, we describe the configuration of the seven-membered ring integrated into the

'Homobenzomorphan is a conventional designation for IO-hydroxy- 4-methyl-2,3,4,5,6,7-hexahydro-l,6-methano-1 H-4-benzazonine.

'TO whom correspondence should be addressed. 3~evis ion received January 29, 1988.

Printed in Canada I lnlprinli nu Canada

I, 1,4-dimethyl-ll-hydroxy-2,3,4,5,6,7-hexahydro-1,6- 1 H-4-benzazonine hydrobromide

11, 1,4,14~-trimethyl-l1-hydroxy-2,3,4,5,6,7-hexahydro-1,6- methano- 1 H-4-benzazonine

111, 1,3-dimethyl-1,2,3,4,5,6-hexahydro-l,5-methano-3-benzazocin- 9-01 (10)

IV, 2,9P-dimethyl-6,7-benzomorphan (8) V, codeine (7)

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1764 CAN. J. CHEM.

TABLE 1. Crystallographic data - -

Parameter Compound I Compound I1

Molecular formula Molecular weight Unit cell a (A) b C

v (A3) z dabs (g ~ m - ~ ) Space group - Radiation, K a (A) T ("C) Crystal size (mm)

C15H21N0.HBr.H20 330.28 Orthorhombic 17.333 (2) 16.652 (1) 10.953 (1) 3161.354 8 1.38 Pbca 1.54178 20 0.2 x 0.1 x 0.2

c16Hz3NO 245.35 Orthorhombic 14.566 (1) 8.347 (1) 11.250 (1) 1367.882 4 1.19 Pna2, 1.54178 20 0.35 X 0.22 X 0.26

multi-ring system of homobenzomorphans. The nrnr results suggest that the same conformations are also present in solution. After earlier statements on the importance of the nitrogen lone-pair orientation in the stereospecific opiate receptor (l2), it was interesting to have an insight into the particular configura- tion of the seven-membered ring integrated into the multi-ring system of compounds I and 11. It was hoped to correlate the above-mentioned differences in the analgesic activity with the presence of 12P-methyl group (C18 in the crystal numbering) in compound 11.

Experimental X-ray dzflaction

The compounds have been synthesized (2) and supplied as racemic mixtures. Recrystallisation of compound I from MeOH-H20 gave a crystalline mixture. On the basis of ref. 3, this mixture was expected to be the (+) and (+/-) bases. The crystal used for the X-ray analysis was from the (+) component. Subsequent photographic osciilationand Weissenberg films confirmed the assumption of a single stereoisomer, and a non-centrosyrnmetric space group was determined.

In case of compound 11, the recrystallisation from MeOH-H20 gave needles of the racemic mixture, confirmed by the determination of a centrosyrnmetric space group. For both compounds, the cell dimensions were refined with 25 reflections measured on the diffrac- tometer. Independent reflections were collected on a Nonius, CAD-4 automatic diffractometer system. Table 1 gives the experimental conditions of the X-ray experiments.

Intensity data were corrected for Lorentz-polarization effects. No corrections were made for absorption or dispersion effects. Direct methods were applied to solve the structures using a MULTAN80 system of programs (4). The coordinates of all non-hydrogen atoms in the two compounds were determined from the best E-map. Further calculations were performed using SHELX (5). The positions of all hydrogen atoms were determined on an electron density difference Fourier map after initial refinement of non-hydrogen atoms. The final structures were refined by using full-matrix least squares with anisotropic temperature factors for non-hydrogen atoms and isotropic temperature factors for hydrogen atoms. The weighting scheme used in the least-squares refinement was w = l / [ u 2 ( ~ ) + 0.001 F '1. Table 2 gives the parameters concerning the refinements. Atomic parameters are given in Table 3 .4

The high negative residual on the last difference Fourier synthesis for compound I appears in a region close to the water O(18) atom. This observation is to be correlated with a high equivalent B for

4Tables of anisotropic temperature factor tables, the structure factor tables, the atomic coordinates of the hydrogen atoms nmr I3c chemical shifts may be purchased from the Depository of Unpublished Data, CISTI, National Research Council of Canada, Ottawa, Ont., Canada KIA OS2.

TABLE 2. Experimental conditions for data collection and refinement

Parameter Compound I Compound I1

F(O,O,O) P (cm-'1 Scan range (deg) Scan rate (deg min-') Aperture of the detector (mm) 20 range (deg) h, k, 1 ranges

Maximum fluctuation of standard reflection (%)

Number of reflections measured Number of reflections observed Threshold: I kg([), k = R = CIAFI/CIF,I R, = [CWAF 2 / C ~ ( ~ , ) 2 ] 1 / 2 (Displacement/u) ,,, (Displacement/u),,,,,, Extreme fluctuations of residual

electron density (e

1376.0 32.97 0.6 + 0.3 tan 0 1 to 10 2.5 + 0.5 tan 0 4- 144 0 s h s 2 1 O s k s 2 0 O S l S 1 3

s 2 3114 2145 2.5 0.031 0.045 0.26 0.00

-0.5 1, 0.17

536.0 4.92 0.6 + 0.3 tan 0 1 to 10 2.5 + 0.5 tan 0 4-144 O s h s 1 7 0 s k s 1 0 O s l S 1 3

s 2 1417 1286 2.5 0.037 0.041 0.19 0.07

-0.16, 0.14

this atom, reflecting an important level of disorder for the solvent molecule.

Nuclear magnetic resonance Proton decoupled carbon-13 nuclear magnetic resonance measure-

ments were performed on a BRUKER CXP200/ASPECT 2000 spectrometer. Chemical shift assignments were facilitated by T I measurements and selective decoupling experiments. Compound I1 was studied in CDC13 from 223 to 323 K and in DMSO-d6 at 323 K whereas compound I was studied from 300 to 373 K in DMSO-d6 and in D20/CD30H (1:3 v/v) at 273 K.

Results Molecular structures

Figure 1 shows the stereoscopic view of the molecular structures for compounds I and 11. The characteristic L-shape is clearly observable, and the methylation at C(10) does not induce significant changes in compound 11. In both compounds, the N-methyl group is pseudo-equatorial with respect to the seven-membered ring C: as a consequence the nitrogen hydro- gen in compound I and the nitrogen lone pair in compound I1 are oriented away from cycle A. In Fig. l a , this orientation has been visualized by placing the proton on the nitrogen pointing towards the bromide ion. In the case of compound I1 repre- sented in Fig. 1 b, a symmetry-related O(1) atom has been used to illustrate-the nitrogen lone pair orientation, involved in an intermolecular hydrogen bond in the crystal.

Figure 2 gives the numbering scheme used. Bond lengths, valence, and torsional angles are given in Tables 4, 5, and 6, respectively. Significant differences in bond lengths and angles are only observed for the seven-membered ring and especially the region of the N(14) atom. Nevertheless, in both compounds, the C ring appears to adopt a "crown" conformation. This can be quantitatively realised examining the seven torsional angles indicated in Table 6.

Crystal packing In the crystal of compound I, the packing of the molecules is

achieved by hydrogen bonds between atoms of Br, 0, and N. Each water oxygen O(18) is bonded to two symmetry-related bromide ions. The water-bromide system constitutes endless

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MICHEL ET AL

TABLE 3. Fractional coordinates ( X lo4) and equivalent Ba for non-hydrogen atoms of compounds I and I1

Compound I Compound I1

Atom x/a Ylb z /c Be, Atom x/a Y lb z/c Beq

FIG. 1. Stereoscopic views of the N-protonated compound I with a facing Br atom ( a ) , and the basic compound 11, ( b ) , with 50% probability ellipsoids for the non-hydrogen atoms.

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CAN. I . CHEM. VOL. 66. 1988

TABLE 5 . Intramolecular valence angles (deg) for compounds I and 11, estimated standard deviations are indicated in parentheses

Angle (deg)

Bonds Compound I Compound I1

FIG. 2. Atom numbering scheme.

TABLE 4. Intramolecular distances (A) for compounds I and I1 estimated standard deviations are indicated

in parentheses

Distance (A)

Bond Compound I Compound I1

chains oriented along the (b,c) diagonal. The molecules are connected to the water-bromide chains by two hydrogen bonds. The first one is formed between the phenolic O(1) as donor and O(18) water atom as acceptor. The second one involves a bromide ion as acceptor, sharing a proton with the basic nitrogen N(14) atom. The resulting extensive network of hydrogen bonds is shown in Fig. 3.

The packing in the crystal of compound I1 is mainly achieved by hydrogen bondings between the phenolic oxygen O(1) and a nitrogen atom N(15). The resulting head-to-tail system gives rise to infinite chains of molecules shown in Fig. 4. Hydroxyl hydrogen atoms H(l) have been included in the packing diagram. Van der Waals interactions assume the cohesion between the chains. Table 7 gives the hydrogen-bond distances and angles obtained for both compounds. The values obtained

TABLE 6. Comparison of the torsional angles (deg) in rings B and C for compounds I and I1

Torsional angle (deg)

Bonds Compound I Compound I1

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TABLE 7. Hydrogen-bond distances (A) and angles (deg) between donor (D) and acceptor (A) atoms

Compound D-H---A L DHA (deg) D---A (A) D-H (A) H---A (A)

FIG. 3. Stereoscopic view of the cell content for compound I, showing the packing and the hydrogen-bonding network (thin lines). Filled circles indicate Br atoms.

for compound I may be compared to those of related 6,7- Dynamic nuclear magnetic resonance analysis (DNMR) benzomorphan compounds published earlier (6). It is interesting The I3C n11-n chemical shifts of compound I (in CDC13) and to observe that the benzomorphan hydrobromide (6) and compound I1 (in DMSO-d6) have been recorded as a function compound I of the present study adopt similar crystal packing. of temperature. The small chemical shift changes are entirely Values obtained for hydrogen-bond geometries (Table 7) are consistent with solvent effects and within the temperature range also very similar. studied show no evidence of conformational changes.

Molecular comparisons Comparisons of the molecular conformations of compounds

I, 11,111, and V have been made using the molecular modelling system SYBYL (1 1). After introduction of the experimental atom coordinates of two molecules into the program, one molecule is subjected to translation and rigid rotation so that the homologous series of atoms of ring A coincide for the two molecules (FIT subprogram of SYBYL). The stereoviews of the resultant pairs of molecules are given in Fig. 5. As can be seen in Fig. 5(a), although packed in very different ways, molecular conformations of compounds I and I1 are very similar. Also, the presence of a 12P-methyl substituent in compound I1 does not induce important modifications on the molecular conformation. Significant differences may be observed on intramolecular bonds C(15)-N(14) and C(13)-N(14): see Table 4. The most different valence angles are C(8)-C(9)-C(15), C(10)- C(9)-C(15), C(6)-C(11)-C(12), C(10)-C(11)-C(12), and C(15)-N(14)-C(17) as can be seen in Table 5. Mean- while, it must be pointed out that the nitrogen atom region of the molecule is mostly affected, as seen from the selected torsional angles given in Table 6.

Discussion Examining the stereoviews of molecular superpositions of

various six-membered piperidyl and seven-membered C ring structures of opiates, it appears that several rules are emerging.

In the case of a piperidyl C ring, the conformation is always "chair". As a consequence and assuming that the N-CH3 group will always be pseudo equatorial, the N lone pair will point away from the A ring if the N is in first position adjacent to the tertiary carbon. This was observed in compound IV (8) and can be seen for compound V in Fig. 5c and has been observed for all known morphine-like molecules (6, 9). If the nitrogen is moved to the second position, for the same chair conformations and the N-CH3 equatorial, the lone-pair will point towards the A ring: see compound I11 (10) on Fig. 5b.

The same rules apply in the case of seven-membered C rings. In compounds I and 11, the complete multi-ring structure adapts itself by modifying the B ring to accommodate the special C ring. This can be seen on superpositions 5b and 5c. For these structures, the "crown" conformation of the seven-membered ring observed in the present study for compounds I and 11, appears to be very rigid and changes very little in solution. The

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CAN. 1. CHEM. VOL. 66, 1988

FIG. 4. Stereoscopic view of the cell content for compound I1 showing the packing and the hydrogen bond involving the hydroxyl group and bridging molecules into infinite chains.

FIG. 5. Stereoviews of pairs of opiates after a least-squares superposition of pairs of homologous atoms in phenyl (A) moiety; ( a ) compound I and compound I1 (dotted lines); (b) compound I and compound 111 (dotted lines); ( c ) compound I and compound IV (dotted lines).

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examination of this C ring shows that a nitrogen atom in a position adjacent to the tertiary carbon, would have its lone pair pointing towards the A ring in order to place the N-CH3 in an equatorial position. If the nitrogen atom is moved to the second position, the lone pair will point away from the A ring, as shown by the structures of I and I1 and as observed in Fig. 5a .

From the present study it follows that the direction (away or toward the A ring) of the electron lone pair of the nitrogen atom in 6-piperidyl and seven-membered C-ring opioids is completely predictable: it depends on the position of the nitrogen atom in the C ring. For the wide variety of modified benzomorphanes synthesized (2), all compounds were shown to be active (2, 3) at various levels, regardless of the nitrogen atom position and hence lone pair orientation. Although a "black or white" answer was not observed, minor structural variations in benzomorphan opiates have been associated with drastic changes in the relative agonist or antagonist properties (14). Following these observations, in the particular case of com- pounds I and I1 the minor distortions observed in the C ring (Table 5 and Fig. 5 a ) have to be considered to account for different activities, the differentiation in the analgesic activity and stereospecificity could also be associated with the presence of the l2p-methyl (C18) group and the steric hindrance of a particular region of space, as invoked in the case of compound IV (8) and other benzomorphans.

Acknowledgements I

Financial support by the Natural Scineces and Engineering Research Council of Canada (NSERC) is gratefully acknow-

ET AL. 1769

ledged. We are grateful to Professor B. Belleau for fruitful discussions and his help in obtaining the compounds.

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