Ardalvn of
TOXICOLOGY
Arch. Toxicol. 36, 97-102 (1976)
9 by Springer-Verlag 1976
X-Ray Crystallographic and Gas Chromatographic--Mass Spectrometric Studies on Norpropoxyphene Gunnar Norheim I and Erik Bye2 1 National Veterinary Institute, P.O. Box 8156, Oslo Dep., Oslo 1, Norway 2 Department of Chemistry, University of Oslo, Oslo 3, Norway
Abstract. The crystal structure of norpropoxyphene maleate is presented. The conformation is discussed in relation to similar compounds. A gas chromatographic-mass spectrometric investigation indicates that earlier proposed metabolites may be formed during the gas chromatographic separation.
Key words: Norpropoxyphene -
Crystal structure -
Gas
chromato-
graphy/Mass spectrometry.
Zusammenfassung. Die Kristallstruktur der Norpropoxyphen-maleat wird beschrieben, und die Konformation dieses Stoffes wird in Relation zu ~ihnlichen Verbindungen diskutiert. Die gaschromatographisch-massenspektrometrische Untersuchung zeigt, dab fr/iher angenommene Metaboliten im Laufe der gaschromatographischen Trennung gebildet werden ktnnen. Dextropropoxyphene (I) is a widely used analgesic with a structure related to methadone (II). In the study of structure-activity relationships (SAR) of analgesics it has been suggested that the effect of methadone depends on a near cyclic structure with a short intramolecular distance between the basic nitrogen atom and the carbonyl carbon atom (Beckett, 1956; Bye, 1974).
I
/N--
Ph-b--f'0 I
I
Ph
N--
Ph0 II
The main metabolic products of methadone are two cyclic metabolites (Beckett et al., 1968 and 1971; Pohland et al., 1971). Dextropropoxyphene is mainly metabolized by N-demethylation, but a cyclic metabolite has also been proposed (McMahon et al., 1973; Nash et al., 1975). By mass spectrometry an amide metabolite (III) resulting from an intramolecular acyl migration in norpropoxyphene, together with
98
G. Norheim and E. Bye
I
I 0
Ph
'
0
Ph
IIl
IV
its dehydrated product (IV), has been identified (Althaus et al., 1969; Bonnichsen et al., 1973). This amide is also formed from norpropoxyphene in aqueous solution with pH above 11 (Grob, 1969). However, as will be shown in the present study, these compounds (III and IV) m a y very well be formed from norpropoxyphene during the gas chromatographic separation. The fact that an intramolecular rearrangement may take place in the norpropoxyphene molecule indicates that a cyclic conformation is involved during the reaction. A thereby close contact between the nitrogen atom and the carbonyl carbon atom is of particular interest in the study of the relation between the structure and the activity of analgesics. Hence the structure determination of norpropoxyphene maleate was carried out by X-ray methods. Previous crystallographic investigations on the hydrochloride and the free base of dextropropoxyphene, however, did not reveal any corresponding short intramolecular distances (Bye, 1973 and 1975).
Material and Methods Norpropoxyphene maleate was kindly suppliedby Eli Lilly and Company (Lot 550-1073-62). The salt could be used for crystallographic studies without recrystallization. For the mass spectrometric investigations norpropoxyphene was extracted with chloroform from three differentsolutions,first from 0.1 N hydrochloric acid solution, second from a 0.1 N sodium carbonate/sodium bicarbonate buffer with pH = 9.9, and third it was extracted from a sodium hydroxide solution with pH above 12.
X-Ray. Three-dimensionalintensity data were collected on a Syntex P1 diffractometer using MoKceradiation. All the calculations were performed on a Cyber-74 computer. Mass Spectrometry. The mass spectra were run on a Varian MAT CH7 mass spectrometer connected with a Varian Aerograph Series 1400 gas chromatograph using a 10% OV-17 column. The helium gas flow was 30 ml/min and the temperature was programmed at 8~ C/min. The mass spectrometer was operated at 70 eV and the ionization temperature was 190~ C.
Results and Discussion The crystal structure of norpropoxyphene maleate was determined by direct methods. A full account for the X-ray analysis is to be presented elsewhere 1 (Bye, 1977). Figure 1 gives a schematic view of the norpropoxyphene molecule as seen in the crystal, where the atomic numbering is indicated. 1 The crystal data are as follows: Nordextropropoxyphene maleate, C21H27NO2-C4H404, orthorhombic, space group P2~2121, cell dimensions: a = 9.365 ~., b = 9.348 .~, c = 27.639 /~
The Crystal Structure of Norpropoxyphene-Maleat C19
99
C6 C8 ,-("~
C20(~
iN
~,._) C17
C7 C5
C2 C9
C15 02 Cl/-, O1 Cll )C2 C13 C12
Fig. 1. Norpropoxyphene maleate molecule as seen in crystal viewed along the z-axis
Table 1. Torsional angles (o) of norpropoxyphene maleate (1) together with those of the hydrochloride (2) and the free base (3) of propoxyphene (Bye, 1973 and 1975)
Atoms
C 1-C2-C3-O1 C2-C3-O2-C4 C3-02-C4-C5 O2-C4-C5-C6 O2-C4-C5-C7 C4-C5-C7-N C5-C7-N-C8 C 3 - O 2 - C 4 - C 10 C3-O2-C4-C17 O 2 - C 4 - C 10-C I 1 C4-C10-Cll-C12 O 2 - C 4 - C 17-C 18 C 11-CI0-C4-C17 C 1 0 - C 4 - C 17-C 18 C6-C5-C7-N
Torsional angles 1
2
- 23.5 - 179.3 178.9 - 179.7 53,6 - 162.0 178.5 61,2 - 62.5 51.2 - 90.4 153.3 173.2 31.5 69.7
-
-
3
5.4 175.1 64.5 174.5 49.4 176.7 173.6 56.3 176.4 42.1 76.2 26.1 71.8 144.0 57.8
-
3.5 180.0 178.6 178.5 57.4 174.2 160.3 63.6 59.7 49.8 90.6 154.5 172.1 32.9 57.4
B o n d l e n g t h s a n d angles h a v e s t a n d a r d values w i t h i n the limits o f e x p e r i m e n t a l e r r o r s . Since t h e p r e s e n t d i s c u s s i o n p r i m a r i l y is c o n c e r n e d w i t h c o n f o r m a t i o n a l features, o n l y the t o r s i o n a l angles are listed. T a b l e 1 s h o w s s o m e o f t h e o b s e r v e d dihedral a n g l e s for n o r p r o p o x y p h e n e t o g e t h e r w i t h t h o s e r e p o r t e d for t h e h y d r o c h l o ride a n d t h e free b a s e o f d e x t r o p r o p o x y p h e n e (Bye, 1973 a n d 1975).
100
G. Norheim and E. Bye
A
AI
BI
Fig. 2. Gas chromatograms of norpropoxyphene extracted from three different solutions using mass spectrometer as detector. Left: A hydrochloric acid solution. Middle: A buffer solution with pH = 9.9. Right: An alkaline solution with pH above 12. B and A represent norpropoxyphene amide (III) and its dehydrated product (IV). Substances were separated on a 10% OV-17 column. Temperature was programmed at 8~ C/rain starting at 180~ C for the left chromatogram and 215 ~ C for the two others
There are only minor conformational differences between the three compounds (see Table 1). The torsional angle C4-C5-C7-N is of particular interest. The propylamino chain is nearly fully extended in the present case and resembles almost entirely that of the hydrochloride and the free base of dextropropoxyphene. No folding of the carbon chain similar to that reported for methadone (Bye, 1974) is observed in the compounds listed in Table 1. The gas chromatograms (as obtained from the mass spectrometer) of the three different extracts of norpropoxyphene are shown in Figure 2. All three chromatograms show two major peaks (A and B). Several mass spectra were run for each of the two peaks, and no variation within each peak could be detected. This indicates essential homogeneity. The mass spectra of the two compounds are given in Figure 3. They are identical with corresponding spectra of norpropoxyphene amide and its dehydrated product (Bonnichsen et al., 1973). Thus it may be concluded that these two compounds may very well be formed within the gas chromatographic column and that it has not been proved that they are metabolites formed in vivo. The cyclic intermediate during the intramolecular acyl migration in norpropoxyphene, together with the cyclic metabolite formed from dinorpropoxyphene (McMahon et al., 1973; Nash et al., 1975) may indicate some degree of conformational flexibility in dextropropoxyphene and some of its metabolites, but the flexibility may be more restricted as compared with methadone and compounds having an optical center similar to methadone (Bye, 1976). Solvent or crystal packing effects may give rise to small conformational variations as the rotational barriers for the bonds C4-CI0 and C2-O2, for example, are not especially high. In reviews on mass spectra of drugs, norpropoxyphene is represented by one or both of the spectra presented in this paper (Finkle et al., 1972; Boerner et al., 1973).
The Crystal Structure of Norpropoxyphene-Maleat
100 %
I01
44
75
M=325
50
234
100 88
25
l
,J.....
I,..... ~ L ,~[.[.hl ..... ~1,,,, I. . . . 50 100 150
,,
I.
~,,
307
ii
250
200
300m/e
100 % 7 5 84 M=307
50
220
25
100 5~
129
91
2~5
:
I
50
100
150
200
307
250
300m/e
Fig. 3. Mass spectra of norpropoxyphene amide (III) (upper) and its dehydrated product (IV) (lower)
The exact position of the double bond in the dehydrated amide (IV) has not been determined. However, the ion m/e 220 m a y be explained by the fragmentation indicated below.
0 "X,--~ Ph VIL~
I
OH + " ~ ,
x'X--Ph--> V L N
ii
"Ph+ -~__ph
I
The characeristic fragments of norpropoxyphene amide (III) is described by Bonnichsen et al. (1973).
Acknowledgements. The authors wish to express their gratitude to Mr. Per Helland at Institute of Clinical Biochemistry, Rikshospitlet, for running the mass spectra.
102
G. Norheim and E. Bye
References Althaus, J. R., Biemann, K., Biller, J., Donaghue, P. F. Evans, D. A., Ftrster, H.-J., Hertz, H. S., Hignite, C. E., Murphy, R. C., Preti, G., Reinhold, V.: Identification of the drug Darvon and its metabolites in the urine of a comatose patient using a gas chromatography-mass spectrometer-computer system. Experientia (Basel) 26, 714-717 (1970) Beckett, A. H.: Analgesics and their antagonists: Some steric and chemical considerations. J. Pharm. Pharmacol. 8, 848-859 (1956) Beckett, A. H., Mitchard, M., Shihab, A. A.: Identification and quantitative determination of some metabolites of methadone, isomethadone, and normethadone. J. Pharm. Pharmacol 23, 347-352 (1971) Beckett, A. H., Taylor, J. F., Casy, A. F., Hassan, M. M. A.: The biotransformation of methadone in man. J. Pharm. Pharmacol. 20, 754-762 (1968) Boerner, U., Abbott, S., Edison, J. C., Becket, C. E., Horio, H. T., Loeffler, K.: Direct mass spectrometric analysis of body fluids from acutely poisoned patients. Clin. chim. Acta 49, 445-454 (1973) Bonnichsen, R., Fri, C.-G., Hj/ilm, R., Petrovics, J., Ryhage, R.." Identification of a dextropropoxyphene metabolite by gas chromatography-mass spectrometry. Z. Rechtsmedizin 71, 270-273 (1973) Bye, E.: Crystal structures of synthetic analgetics. I. Dextropropoxyphene hydrochloride. Acta chem. scand. 27, 3403 3413 (1973) Bye, E.: Crystal structures of synthetic analgetics. II. 1-Methadone. Acta chem. scand. B 28, 5--12 (1974) Bye, E.: Crystal structures of synthetic analgetics. IV. Dextropropoxyphene. Acta chem. scand. B 29, 556--560 (1975) Bye, E.: On the crystal structure of an analgetic metabolite, norpropoxyphene maleate. Acta chem. scand. B 30, 95--100 (1976) Bye, E.: Crystal structures of synthetic analgetics. V. Dextromoramide. Aeta chem. scand. In press (1977) Finkle, B. S., Taylor, D. M.: A GC/MS reference data system for the identification of drugs of abuse. J. Chromatogr. Sci. 10, 312-333 (1972) Grob, C. A.: Mechanisms and stereochemistry of heterolytic fragmentation. Angew. Chem. (International Ed.) 8, 535-546 (1969) McMahon, R. E., Sullivan, H. R., Due, S. Lo, Marshall, F. J.: The metabolite pattern of d-propoxyphene in man. The use of heavy isotopes in drug disposition studies. Life Sci. 12, 463-473 (1973) Nash, J. F., Bennett, I. F., Bopp, R. J., Brunson, M. K., Sullivan, H. R.: Quantitation of propoxyphene and its major metabolites in heroin addict plasma after large dose administration of propoxyphene napsylate. J. pharm. Sci. 64, 429-433 (1975) Pohland, A., Boaz, H. E., Sullivan, H. R.: Synthesis and identification of metabolites resulting from the ,biotransformation of DL-methadone in man and the rat. J. Med. Chem. 14, 194-197 (1971) Received December 1, 1976
TOXICOLOGY
Arch. Toxicol. 36, 97-102 (1976)
9 by Springer-Verlag 1976
X-Ray Crystallographic and Gas Chromatographic--Mass Spectrometric Studies on Norpropoxyphene Gunnar Norheim I and Erik Bye2 1 National Veterinary Institute, P.O. Box 8156, Oslo Dep., Oslo 1, Norway 2 Department of Chemistry, University of Oslo, Oslo 3, Norway
Abstract. The crystal structure of norpropoxyphene maleate is presented. The conformation is discussed in relation to similar compounds. A gas chromatographic-mass spectrometric investigation indicates that earlier proposed metabolites may be formed during the gas chromatographic separation.
Key words: Norpropoxyphene -
Crystal structure -
Gas
chromato-
graphy/Mass spectrometry.
Zusammenfassung. Die Kristallstruktur der Norpropoxyphen-maleat wird beschrieben, und die Konformation dieses Stoffes wird in Relation zu ~ihnlichen Verbindungen diskutiert. Die gaschromatographisch-massenspektrometrische Untersuchung zeigt, dab fr/iher angenommene Metaboliten im Laufe der gaschromatographischen Trennung gebildet werden ktnnen. Dextropropoxyphene (I) is a widely used analgesic with a structure related to methadone (II). In the study of structure-activity relationships (SAR) of analgesics it has been suggested that the effect of methadone depends on a near cyclic structure with a short intramolecular distance between the basic nitrogen atom and the carbonyl carbon atom (Beckett, 1956; Bye, 1974).
I
/N--
Ph-b--f'0 I
I
Ph
N--
Ph0 II
The main metabolic products of methadone are two cyclic metabolites (Beckett et al., 1968 and 1971; Pohland et al., 1971). Dextropropoxyphene is mainly metabolized by N-demethylation, but a cyclic metabolite has also been proposed (McMahon et al., 1973; Nash et al., 1975). By mass spectrometry an amide metabolite (III) resulting from an intramolecular acyl migration in norpropoxyphene, together with
98
G. Norheim and E. Bye
I
I 0
Ph
'
0
Ph
IIl
IV
its dehydrated product (IV), has been identified (Althaus et al., 1969; Bonnichsen et al., 1973). This amide is also formed from norpropoxyphene in aqueous solution with pH above 11 (Grob, 1969). However, as will be shown in the present study, these compounds (III and IV) m a y very well be formed from norpropoxyphene during the gas chromatographic separation. The fact that an intramolecular rearrangement may take place in the norpropoxyphene molecule indicates that a cyclic conformation is involved during the reaction. A thereby close contact between the nitrogen atom and the carbonyl carbon atom is of particular interest in the study of the relation between the structure and the activity of analgesics. Hence the structure determination of norpropoxyphene maleate was carried out by X-ray methods. Previous crystallographic investigations on the hydrochloride and the free base of dextropropoxyphene, however, did not reveal any corresponding short intramolecular distances (Bye, 1973 and 1975).
Material and Methods Norpropoxyphene maleate was kindly suppliedby Eli Lilly and Company (Lot 550-1073-62). The salt could be used for crystallographic studies without recrystallization. For the mass spectrometric investigations norpropoxyphene was extracted with chloroform from three differentsolutions,first from 0.1 N hydrochloric acid solution, second from a 0.1 N sodium carbonate/sodium bicarbonate buffer with pH = 9.9, and third it was extracted from a sodium hydroxide solution with pH above 12.
X-Ray. Three-dimensionalintensity data were collected on a Syntex P1 diffractometer using MoKceradiation. All the calculations were performed on a Cyber-74 computer. Mass Spectrometry. The mass spectra were run on a Varian MAT CH7 mass spectrometer connected with a Varian Aerograph Series 1400 gas chromatograph using a 10% OV-17 column. The helium gas flow was 30 ml/min and the temperature was programmed at 8~ C/min. The mass spectrometer was operated at 70 eV and the ionization temperature was 190~ C.
Results and Discussion The crystal structure of norpropoxyphene maleate was determined by direct methods. A full account for the X-ray analysis is to be presented elsewhere 1 (Bye, 1977). Figure 1 gives a schematic view of the norpropoxyphene molecule as seen in the crystal, where the atomic numbering is indicated. 1 The crystal data are as follows: Nordextropropoxyphene maleate, C21H27NO2-C4H404, orthorhombic, space group P2~2121, cell dimensions: a = 9.365 ~., b = 9.348 .~, c = 27.639 /~
The Crystal Structure of Norpropoxyphene-Maleat C19
99
C6 C8 ,-("~
C20(~
iN
~,._) C17
C7 C5
C2 C9
C15 02 Cl/-, O1 Cll )C2 C13 C12
Fig. 1. Norpropoxyphene maleate molecule as seen in crystal viewed along the z-axis
Table 1. Torsional angles (o) of norpropoxyphene maleate (1) together with those of the hydrochloride (2) and the free base (3) of propoxyphene (Bye, 1973 and 1975)
Atoms
C 1-C2-C3-O1 C2-C3-O2-C4 C3-02-C4-C5 O2-C4-C5-C6 O2-C4-C5-C7 C4-C5-C7-N C5-C7-N-C8 C 3 - O 2 - C 4 - C 10 C3-O2-C4-C17 O 2 - C 4 - C 10-C I 1 C4-C10-Cll-C12 O 2 - C 4 - C 17-C 18 C 11-CI0-C4-C17 C 1 0 - C 4 - C 17-C 18 C6-C5-C7-N
Torsional angles 1
2
- 23.5 - 179.3 178.9 - 179.7 53,6 - 162.0 178.5 61,2 - 62.5 51.2 - 90.4 153.3 173.2 31.5 69.7
-
-
3
5.4 175.1 64.5 174.5 49.4 176.7 173.6 56.3 176.4 42.1 76.2 26.1 71.8 144.0 57.8
-
3.5 180.0 178.6 178.5 57.4 174.2 160.3 63.6 59.7 49.8 90.6 154.5 172.1 32.9 57.4
B o n d l e n g t h s a n d angles h a v e s t a n d a r d values w i t h i n the limits o f e x p e r i m e n t a l e r r o r s . Since t h e p r e s e n t d i s c u s s i o n p r i m a r i l y is c o n c e r n e d w i t h c o n f o r m a t i o n a l features, o n l y the t o r s i o n a l angles are listed. T a b l e 1 s h o w s s o m e o f t h e o b s e r v e d dihedral a n g l e s for n o r p r o p o x y p h e n e t o g e t h e r w i t h t h o s e r e p o r t e d for t h e h y d r o c h l o ride a n d t h e free b a s e o f d e x t r o p r o p o x y p h e n e (Bye, 1973 a n d 1975).
100
G. Norheim and E. Bye
A
AI
BI
Fig. 2. Gas chromatograms of norpropoxyphene extracted from three different solutions using mass spectrometer as detector. Left: A hydrochloric acid solution. Middle: A buffer solution with pH = 9.9. Right: An alkaline solution with pH above 12. B and A represent norpropoxyphene amide (III) and its dehydrated product (IV). Substances were separated on a 10% OV-17 column. Temperature was programmed at 8~ C/rain starting at 180~ C for the left chromatogram and 215 ~ C for the two others
There are only minor conformational differences between the three compounds (see Table 1). The torsional angle C4-C5-C7-N is of particular interest. The propylamino chain is nearly fully extended in the present case and resembles almost entirely that of the hydrochloride and the free base of dextropropoxyphene. No folding of the carbon chain similar to that reported for methadone (Bye, 1974) is observed in the compounds listed in Table 1. The gas chromatograms (as obtained from the mass spectrometer) of the three different extracts of norpropoxyphene are shown in Figure 2. All three chromatograms show two major peaks (A and B). Several mass spectra were run for each of the two peaks, and no variation within each peak could be detected. This indicates essential homogeneity. The mass spectra of the two compounds are given in Figure 3. They are identical with corresponding spectra of norpropoxyphene amide and its dehydrated product (Bonnichsen et al., 1973). Thus it may be concluded that these two compounds may very well be formed within the gas chromatographic column and that it has not been proved that they are metabolites formed in vivo. The cyclic intermediate during the intramolecular acyl migration in norpropoxyphene, together with the cyclic metabolite formed from dinorpropoxyphene (McMahon et al., 1973; Nash et al., 1975) may indicate some degree of conformational flexibility in dextropropoxyphene and some of its metabolites, but the flexibility may be more restricted as compared with methadone and compounds having an optical center similar to methadone (Bye, 1976). Solvent or crystal packing effects may give rise to small conformational variations as the rotational barriers for the bonds C4-CI0 and C2-O2, for example, are not especially high. In reviews on mass spectra of drugs, norpropoxyphene is represented by one or both of the spectra presented in this paper (Finkle et al., 1972; Boerner et al., 1973).
The Crystal Structure of Norpropoxyphene-Maleat
100 %
I01
44
75
M=325
50
234
100 88
25
l
,J.....
I,..... ~ L ,~[.[.hl ..... ~1,,,, I. . . . 50 100 150
,,
I.
~,,
307
ii
250
200
300m/e
100 % 7 5 84 M=307
50
220
25
100 5~
129
91
2~5
:
I
50
100
150
200
307
250
300m/e
Fig. 3. Mass spectra of norpropoxyphene amide (III) (upper) and its dehydrated product (IV) (lower)
The exact position of the double bond in the dehydrated amide (IV) has not been determined. However, the ion m/e 220 m a y be explained by the fragmentation indicated below.
0 "X,--~ Ph VIL~
I
OH + " ~ ,
x'X--Ph--> V L N
ii
"Ph+ -~__ph
I
The characeristic fragments of norpropoxyphene amide (III) is described by Bonnichsen et al. (1973).
Acknowledgements. The authors wish to express their gratitude to Mr. Per Helland at Institute of Clinical Biochemistry, Rikshospitlet, for running the mass spectra.
102
G. Norheim and E. Bye
References Althaus, J. R., Biemann, K., Biller, J., Donaghue, P. F. Evans, D. A., Ftrster, H.-J., Hertz, H. S., Hignite, C. E., Murphy, R. C., Preti, G., Reinhold, V.: Identification of the drug Darvon and its metabolites in the urine of a comatose patient using a gas chromatography-mass spectrometer-computer system. Experientia (Basel) 26, 714-717 (1970) Beckett, A. H.: Analgesics and their antagonists: Some steric and chemical considerations. J. Pharm. Pharmacol. 8, 848-859 (1956) Beckett, A. H., Mitchard, M., Shihab, A. A.: Identification and quantitative determination of some metabolites of methadone, isomethadone, and normethadone. J. Pharm. Pharmacol 23, 347-352 (1971) Beckett, A. H., Taylor, J. F., Casy, A. F., Hassan, M. M. A.: The biotransformation of methadone in man. J. Pharm. Pharmacol. 20, 754-762 (1968) Boerner, U., Abbott, S., Edison, J. C., Becket, C. E., Horio, H. T., Loeffler, K.: Direct mass spectrometric analysis of body fluids from acutely poisoned patients. Clin. chim. Acta 49, 445-454 (1973) Bonnichsen, R., Fri, C.-G., Hj/ilm, R., Petrovics, J., Ryhage, R.." Identification of a dextropropoxyphene metabolite by gas chromatography-mass spectrometry. Z. Rechtsmedizin 71, 270-273 (1973) Bye, E.: Crystal structures of synthetic analgetics. I. Dextropropoxyphene hydrochloride. Acta chem. scand. 27, 3403 3413 (1973) Bye, E.: Crystal structures of synthetic analgetics. II. 1-Methadone. Acta chem. scand. B 28, 5--12 (1974) Bye, E.: Crystal structures of synthetic analgetics. IV. Dextropropoxyphene. Acta chem. scand. B 29, 556--560 (1975) Bye, E.: On the crystal structure of an analgetic metabolite, norpropoxyphene maleate. Acta chem. scand. B 30, 95--100 (1976) Bye, E.: Crystal structures of synthetic analgetics. V. Dextromoramide. Aeta chem. scand. In press (1977) Finkle, B. S., Taylor, D. M.: A GC/MS reference data system for the identification of drugs of abuse. J. Chromatogr. Sci. 10, 312-333 (1972) Grob, C. A.: Mechanisms and stereochemistry of heterolytic fragmentation. Angew. Chem. (International Ed.) 8, 535-546 (1969) McMahon, R. E., Sullivan, H. R., Due, S. Lo, Marshall, F. J.: The metabolite pattern of d-propoxyphene in man. The use of heavy isotopes in drug disposition studies. Life Sci. 12, 463-473 (1973) Nash, J. F., Bennett, I. F., Bopp, R. J., Brunson, M. K., Sullivan, H. R.: Quantitation of propoxyphene and its major metabolites in heroin addict plasma after large dose administration of propoxyphene napsylate. J. pharm. Sci. 64, 429-433 (1975) Pohland, A., Boaz, H. E., Sullivan, H. R.: Synthesis and identification of metabolites resulting from the ,biotransformation of DL-methadone in man and the rat. J. Med. Chem. 14, 194-197 (1971) Received December 1, 1976
