3-
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 7 565
AND ~ - M E T H Y L - ~ , ~ - B E N Z O M O R P H A N S
Synthesis and Analgetic Activity of 3- and 4-Methyl-6,7-benzomorphans
ROBERTT. PARFITT*AND SUSANM. WALTERS Pharmaceutical Chemistry, University of Strathclyde, Glusgow C J . , Scotland Received November 12, 19'70
2,5-Dimethyl-6,7-benzomorphansbearing piperidine bridge 3- and 4-Me substituents (4 and 8) have been synthesized via the 2-benzyltetrahydropyridines 3a, 3b, and 7. N-Phenethyl (13a and 13b), dimethylallyl (loa and lob), and cyclopropylmethyl (14a and 14b) derivatives were also prepared, and the methiodides 17a and 17b were degraded to the corresponding dihydronaphthalenes (18a and 18b). Compound 14a exhibits analgetic activity equiv to about half that of morphine.
hydropyridines formed from NaBH4 reduction of a Synthetic studies in the 6,7-benzomorphans have single dihydropyridine precursor have been reported resulted in potent analgetic agents in which analgesia recently." Cyclization of the isomeric mixture to a and physical dependence have, to a large extent, been single product ( =k)-2,3,5-trimethyl-6,7-benzomorphan This has been particularly true in the (4) in refluxing HBr in aq HOAc occurred smoothly case of analgetics of the antagonist type which are not capable of supporting morphine-like dependen~e.~15 and in high yield. ( =t)-2,4,5-Trimethyl-6,7-benzomorphan (8), our secFurthermore, recent investigations have uncovered a ond objective, was synthesized via a modified Grewe surprising level of analgetic potency in 6,7-benzomorroute. NaBH4 reduction of 3,klutidine methiodide phans lacking a quaternary C at C-5 and bearing only (5) in the presence of KCN gave the nitrile 6 together a secondary N,6,7and in a series of B-norbenzomorthe exwith 1,3,4-trimethyl-1,2,5,6-tetrahydropyridine, pham8 pected by-product.'Z Treatment of 6 with COH5CHzI n order to extend the present knowledge of strucMgC1 afforded the required benzyltetrahydropyridine ture-activity relationships in the 6,7-benzomorphans, 7, which cyclized readily in boiling 48% aq HBr to 8 particularly the effect of steric crowding of N, we have in high yield. synthesized novel pairs of isomeric compounds possessIt is now well established that variation of the bening either a 3- or 4-Me substituent. These compounds zomorphan N-substituent is able to afford both agonistcorrespond to amidone and isoamidone analogs. and antagonist-type analgeti~s.~JI n our series 2 Alkylation of 1-methyl-2-tetralone by 2-chlorocompounds in each category were investigated; N-Me N,N-dimethylpropylamine following the standard proand N-phenethyl as agonist and N-cyclopropylmethyl cedureg gave the expected mixture of l-methyl-land N-dimethylallyl as antagonist agents. (2-dimethylaminopropy1)- and l-methyl-l-(2-dimethylFollowing the standard procedure N-demethylation aminoisopropyl)-2-tetralones, which could be separated of 4 and 8 was accomplished by the von Braun CNBr only with difficulty and in low yields. The Grewe method to yield 3,5-dimethyl- and 4,5-dimethyl-6,7route therefore appeared to be a more attractive possibenzomorphan (9a and 9b, respectively) via their isobility. Treatment of C6H&H2RlgCl with 1,2,4-trimethylpyr- lated N-nitriles. Both 9a and 9b were converted to the corresponding idinium iodide (1) gave 75% of the desired 2-benzyl2-dimethylallyl derivatives (loa and lob) by direct 1,4,6-trimethyl-1,2-dihydropyridine(2) as its crystalalkylation with l-bromo-3-methylbut-2-ene in DMF. line perchlorate. Pmr examination of 2.base in Preparation of the 2-phenethyl (13a and 13b) and CDC& confirmed the assigned structure. The princi2-cyclopropylmethyl (14a and 14b) derivatives was ple features were a finely split doublet at 6 1.70 ( J = achieved through the corresponding 2-phenacetyl1.2 He) for 4-CH3, and a broad singlet a t 6 1.87 for ( l l a and l l b ) and 2-cyclopropylcarbony1-(12a and 12b) 6-CH3. Conversion of 2.base to the perchlorate re6,7-benzomorphans, by direct acylation followed by sulted in spectral shifts similar to those reported previLAH reduction of the amide intermediates. ously.'O BH4- reduction of 2 gave an approximately On examination of the pmr spectra (Table I) of both equimolar mixture of the tetrahydropyridines 3a and series of benzomorphans it was apparent that the 4-CH3 3b as indicated by pmr examination. The doublets absorption always occurred in a strongly shielded posi( J = 7 Hz) corresponding to 6-CH3 in 3a and 3b occurred at 6 1.10 and 1.00,respectively. Similar isomeric tion at approximately 6 0.6. I n the 3-methyl-6,7mixtures of 4-alkyl-2-p-methoxybenzyl-1-methyltetra- benzomorphans, where the 3-CH3 group is analogous to that found in amidone, the 3-CH3 resonance signal was * Address correspondence to Chemical Research Department, Pfizer Ltd., seen in an unexceptional position. The 5-CH3 shift Sandwich, K e n t , England. (1) N . B. Eddy a n d E . L. M a y "Synthetic Analgesics, P a r t I I B , 6,7remains constant in both series. During synthetic Benzomorphans," Pergamon Press, London, 1966, pp 138 ff. studies it was anticipated that pairs of compounds iso(2) E . L M a y a n d N . B. E d d y , J. Med. Chem., 9, 851 (1966). steric about positions 3 and 4 would be generated in the (3) J . H . Ager, A E Jacobson, and E . L. M a y , abzd , 12, 288 (1969). (4) 5. Archer, N. F. Albertson, L. S. Harris, A K . Pierson, a n d J. G. final cyclization steps (i.e., 3 -+ 4 and 7 + 8). I n each Bird, zbid., 7 , 123 (1964). instance only a single isomer was isolated, although (5) M . Gates and T. A. Montzka, zbzd., 1, 127 (1964). traces of the second isomer were apparent in pmr spec(6) K . Kanematsu, R. T. Parfitt, A. E . Jacobson, J. H. Ager, a n d E. L. M a y , J. Amer. Chem. Soc., 90, 1064 (1968). tra of the crude reaction product. The deshielding (7) K . Kanematsu, M . Takeda, A. E. Jacobson, a n d E . L. M a y , J. Med. which occurs in the case of the 4-CH3 signal may be Chem., 12, 405 (1969). (8) A . E . Jacobson a n d M . Mokotoff, zbid., 18, 7 (1970). (9) E . L. M a y a n d J. G. Murphy, J . Ore. Chem., 20, 257 (1955). (10) A. E. Jacobson a n d R . T. Parfitt, zbzd., 82, 1894 (1967).
(11) M . Takeda, A . E. Jacobson, E. L. M a y , abad., 84, 4161 (1969). (12) E . H. Fry, zbzd., 29, 1647 (1964).
PARFITT AND WALTERS
566 Journal of Medicinal Chemistry, 1971, Vol. 14, No. 7
SCHEME I
TABLE I CHEMICAL SHIFTS (6) OF THE 3-,4- AND 5-CH3 PROTONS (10% SOLUTIONS I N CDC13) 3-CH3, d , J = 6.5 Hz
Compd
4 8
0.92
Sa
0.92
4-CHs, d , J = 6.5 Hz
5-CHa,
0.60
9b
0.61 0.96
1Oa
10b 13a 13b 14a 14b
8
1.37 1.36 1.38 1.35 1.36 1.35 1.38 1.36 1.37 1.35
0.60 0.98 0.62
0.92 0.60
explained by reference t o Dreiding stereomodels and the Johnson-Bovey shielding map.13 When the benzomorphan piperidine ring is in the favorable chair conformation and the 4-Me is equatorial, the latter group resides in the positive shielding cone above the plane of the aromatic ring. The 3-CH3, on the other hand, has a normal proton resonance signal a t about 6 1. This also indicates an equatorial conformation (piperidine chair), since had the group been in an axial position then it too would have overhung the aromatic ring and would have been subjected to a considerable shielding influence. I n both series of congeners, therefore, the epimers isolated bear their 3- or 4-Me groups in an equatorial conformation on the piperidine chair (15 and 16, respectively).
4
16
15
The methiodides (17a and 17b) of the 6,7-benzomorphans 4 and 8 on treatment with thallous hydroxide gave Hofmann elimination products 18a and 18b, respectively. I n its pmr spectrum the dihydronaph-
SCHEME 11
H3C,I-,CH3
\ /
9
CH3
R
17
R 18
a,R=CH,; R' = H
b,R'=CH,;R=H
thalene 18a shows little change in the chemical shifts of the Ale groups corresponding to the benzomorphan 3-C& (6 0.95) and 5-CH3 (6 1.42) from those of the parent compound 4 (6 0.92 and 6 1.37). The isomeric tetrahydronaphthalene 18b, on the other hand, exhibits a shift of the 4-CH3 signal from the aromatic ring-shielded position (6 0.60) in 8 to 6 0.92 in the nonconstrained state. I n both Hofmann elimination (13) C. E. Johnson and F. A . Bovey, J . Chem. Phys., 29, 1012 (1958).
IO, R2 = CHZCH=C(CHJ, 11, RZ = COCH&H, 12,RZ=COd 13, R2= CH$H,CsH, 14, R2 = C H Z q a,R, = CH,; R' = H
b,R = H; R'= CH,
products the olefinic proton shifts and coupling patterns are consistent with the structures 18a and 18b. Biological Results.-2,4,5-Trimethyl-6,7-benzomorphan (8) hydrochloride exhibits an analgetic potency almost 3 times greater than that of the isomer 4, in which hindrance of the tertiary N is apparent, and approximately twice that of codeine .HCl. Surpris-
3- AND
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 7 567
4-METHYL-6,7-BENZOMORPHANS
The aq layer gave 0.4 g of product on standing making the total ingly the phenethyl derivatives in both series (13a yield of 2,51.4 g (75%). I t was recrystd from MeOH as colorless and 13b) are without activity at subtoxic doses. AlC, H, N. plates, mp 165-168". Anal. (Cl~H2&lNO~) though these analogs lack a phenolic OH, significant 2-Benzyl-l,4,6-trimethyl-l,2,3,6-tetrahydropyridine(3b) and activity was expected. -1,2,5,64etrahydropyridine (ta).-To a stirred suspension of 2 (30.7 g) in a mixt of MeOH (92 ml) and aq 1 N NaOH (272 ml) The most significant result was the high level of was added NaBH4 (5 g) during 20 min. The stirred mixt agonist potency, approximately 0.5 that of morphine, was maintained at 55-60' for 30 min, dild with HzO (200 ml), shown by 2-cyclopropylmethyl-3,5-dimethyl-6,7-ben- and extd with Et20 (4 X 200 ml). The exts were dried (NaaS04), zomorphan (14a) hydrobromide. I n contrast, the and the solvent was removed to give 17.9 g of pr0duct.t The mixed isomers were cyclized without sepn. isomeric 14b was inactive a t subtoxic doses. KOsup2,3,5-Trimethyl-6,7-benzomorphan .HBr (4.HBr).-A mixt of pression of abstinence syndrome was observed when 3a and 3b (17.9 g), 48Y0 aq HBr (50 ml), and 45% HBr in AcOH 14a was substituted in monkeys physically dependent (30 ml) was heated under reflux for 48 hr. The cooled soln was on morphine. It would be reasonable to expect analbasified with "4OH and extd with Et20 (3 X 100 ml). The gesic potency to be enhanced in this series by the inEt20 soln was extd with 2 N HC1 (3 X 100 ml), and the combined acid soln was basified with NHIOH. Extn with Et20 (3 x 100 clusion of a 2-phenolic hydroxyl group. ml) followed by evapn of the dried (NaZSO,) exts afforded crude Hindrance of the tertiary N in morphine-like anal4 (16.8 g, 94y0). Distn over a short path [SS" (1.2 mm)] gave getics may have some bearing on both the level and type pure 4 base (12.3 g, 73%). The hydrobromide sepd as colorless of analgetic activity exhibited. Further investigations plates from EtOH-Et20 and had mp 180-182". Anal. (Cl5HZ2BrN) C, H, N. The methiodide was prepd in dry Me2C0 and of this parameter, therefore, are in progress.
TABLE I1 ANALGETIC ACTIVITY OF SOME3- A N D 4-METHYL-6,7-BENZOMORPHANS
ED60," Compd
mg/kg, sc
4.HBr 11.9 8.HC1 4.2 lOa.HC1 b 10b.HCl 19.2 C 13a.HBr 13b.HC1 C 14a.HBr 2.2 14b.HC1 b Xorphine .HC1 1.2 Codeine HC1 7.5 a The compds were tested for analgetic activity by the EddyLeimbach (C. E. Johnson and F. A. Bovey, J . Chem. Phys., 29, 1012 (1958)) mouse hot-plate procedure employing Caesarian Derived General Purpose (CDCP) mice (N. B. Eddy and D. Leimbach, J . Pharmacol. Exp. Ther., 107, 385 (1953)). The hot-plate test is a nonspecific screen for analgesia and it is possible that antagonist agents may exhibit activity by virtue of muscle relaxant properties. Further testing is planned by a modified Nilsen procedure (P. Xilsen, Acta Pharmacol. Toxicol., 18, 10 (1961); G. C. Holsky, J. A. Richman, C. D. Lunsford, H. Jenkins, R. P. hfays, W. H. Funderburk, and D. N. Johnson, J. Med. Chem., 71, 472 (1968); E. L. May, personal communication). Inactive at subtoxic dose
