Influence of 6-Azido and 6-Thiocyanato Substitution on Progestational and Corticoid Activities and a Structure-Activity Correlation in the A6-6-Substituted Progestational Series (ieorge Teutsch,? Lois Weber. Geoffrey Page.: Elliot L. Shapiro.* Hershel L. Herzog. l n t u r a i Produc t c KP\enrch I l e p a r t m ( ~ n t
The preparation and biologic (progestin. antiandrogen. and corticoid) activit? of some 6-azido- and 6-thiocyanate14,6 steroids are described. The comparative order of activities of the 6-substituted progestins is tabulated as follows: 6-Me > 6-C1 > 6-F > 6-Br > 6 - x ~> 6-OCH3 > 6 - S C S > 6-CF3 > 6-CN > 6-C-NOMe > 6-H. > 6-CHO. 6-OC2H5 > 6-OCOCH3 > 6-NHCOCH3; in contrast, for the described corticoids. 6-N3 > 6-CI. The steric and electronic influences of 6 substituents on progestational activity are discussed. with particular emphasis given to the steric influence by empirically defining their relative spacial requirements.
Substitution a t the 6 position has been known to have a dominant and controlling effect on the dimensions of progestational activity among the 17n-acetoxyprogesterones and their 16-alkylated counterparts. Our own studies have centered around t h e 6-substituted derivatives of 6-dehydro-16-methyIene-17tr-acetoxyprogesterone. a series of compounds which has displayed especially pronounced potency. In this paper we bring together our biological findings and attempt to define the steric and electronic character of 6 substitution which leads to maximum progestational (Clauberg) potency within this series.
To gain a greater insight into the basis of bioactivity in this series. we have now prepared derivatives containing the pseudo-halo substituents. 6-azido and 6-thiocyanato. To accomplish this we followed the principles of the method reported from these laboratories'~3 and also employed independently by o t h e r s 4 Reaction of the 6.70oxide 15 with N a S a in aqueous MeOH containing AcOH gave the 6ij-azido-7ct-hydroxy 2a in 86% yield. The conf'igurational assignment, establishzd by nmr, was consistent with related diaxial openings of 6cu.7cu-oxides. In the absence of AcOH. the basic NaiY-MeOH-HzO reaction sys-
Schemr I
CHI
I
CH t
I
CH
I
i'=O
t S h e r i n g Postdoctoral Fellow. 19GS-1969 1 Scherinr Postdoctoral Fellow. 1970.
tem caused some solvolysis of the 17-acetate group in ad dition to the desired opening of the 6n.7~u-oxide.With thik
Journal ofMedicinal Chemistry, 1973, Vol. f6, No. 12 1371
s6-6-Substit~tedProgestational Series
Table I. Progestational and Antiandrogenic Activities ProgestaCompd tional” no. im sb
4a 4b 4C
7a 7c 4d
20 12 77f 10 145h 1
sv 40 61 360
AntiandrogenkcJ (as % of control)$ VP LA Adrenals 62 65 460
42 84 42s
Table 11. Correlation of Progestational Activity of Compound 4 with Steric Effects
c6-x
25 79 37
X CHI
76
81
94
99
aprogestational activity was determined in immature rabbits by the method of M. K . McPhail, J.Physiol. ( L o n d o n ) , 83, 145 (1934), with progesterone = 1. 6Reference 12 cites the statistical method used t o obtain the results presented here. ref 3, see ref 3-5. dMale rats (Charles River C D strain) 21-28 days old and weighing approximately 60 g were used to assess the ability of the compounds to inhibit endogenous androgens. The compound was suspended in an aqueous suspending vehicle (0.9% NaCl, 0.5% carboxymethylcellulose, 0.4% polysorbate 80, and 0.9% benzyl alcohol) and injected sc each day a t 10 mg/kg for 3 weeks. Twenty-four hours following the last drug treatment, the seminal vesicles (SV), ventral prostate (VP), levator ani (LA), and adrenals were removed and weighed. BWith controls taken as 100, the greater the activity, the less the percentage. fReference 3 and references cited therein. gReference 3. *Reference 12. NaN3-MeOH-HzO system, the bisoxide 5 afforded selective opening of the 6,7-oxide, yielding the corresponding azidohydrin 6 (R = HI (Scheme I). We chose to study the preparation of the 6-dehydro-6azido 4a from 3a (7-acetate and 7-mesylate, prepared by esterification of the 7a-hydroxyl group of 2a) by base-catalyzed elimination of the 7 substituent. In our first basecatalyzed elimination attempts,§ treatment of the 7amesylate 3a and the 7a-tosylate 6 with N a H in dioxane caused, instead, rearrangement of the 6-azide group to the 4 position,7 accompanied by elimination of the ’i substituent. However, our goal was achieved with tetramethylammonium fluoride (TMAF),’ anhydrous or hydrated,** in acetonitrile at room temperature or 6 0 ” , t t the desired elimination?? being effected in good yield from the ‘i-acetate 3a and the 7-mesylate 3a, each giving the diene 4a. The 7u,l7-diacetate 3a was readily available to us from 6a (R = H, as well as from 2a mentioned previously) by ptoluenesulfonic acid (p-TSA) catalyzed opening of the l&,l’ia-oxide concomitant with acetylationlO [trifluoroacetic anhydride (TFAA)-AcOH] at the 7 and 17 position. Surprisingly, tetramethylammonium chloride (TMACl) also transformed the 7-mesylate 3a into 4a (58%),accompanied by about 5% of the 4 - a z i d 0 - 1 ~ 9product.7.8$ ~ On the other hand, dehydration of 2a to l a could not be effected by TMAF-CH3CN. Apparently the success of the elimination reaction depends as much on the leaving group qualities of the 7u substituent as on the basicity of 8 Drefahl. et al. (ref 6J, report the elimination of 7a-OH with concentrated HCI-dioxane-AcOH to afford the 6-azido-A4,6 3-ketone in the 16-desmethylene series. = T h e use of TMAF as a proton abstractor has heen reported by Hajami. et ni , in ref 8. ** Aldrich Chemical Co., Milwaukee. b‘is. t+Prolonged heating of 1 at 60” with TMAF-CH&S affords the sidechain lactone 20 in 25% yield. the structure being suggested from the nmr: 1.47 (20-CH3, geminal to hydroxyl grouping). Cf. ref 9 for this type of basecatalyzed cyclization using NaH and NaOH. Thus, TMAF in CH&N is a sufficiently strong base to catalyze Claisen condensation. I:The generality of TMAF for generation of a 6-substituted A 4 3 system was demonstrated by the deacetox?lation of 3c to give Jc in 85% yield after 24 hr at room temperature. $I Hayami, et al.,” report the use of tetramethylammonium fluoride in the generation of styrene from 2-phenethyl bromide but that tetraethylammonium chloride and bromide did not generate styrene,
bond Progesta- axis“ VOl, A 3 b , d tional distance, HalfCircumact. && sphere Cylinder ferencec
F Br NB
91 77 55 42 20
OCHI SCN CF3 CN
14 12 11 6
c1
C-NOMe OC2Hs H CHO OC(=O)CHI NCOCHI
2 1 1 1
0.2 0.1
3.00 2.71 1.99 3.02 2.914.34 2.81 4.45 3.55 3.11
31 42 17 58 117 106 246 52
1.493.14 513 290 6 48 290 298
4.31 3.60 1.44 3.28 3.60 3.62
3.82
8.67 6.09 4.27 7.09 15.64 15.13 12.94 11.93 4.84 28.57 23.42 2.32 9.92 23.36 23.67
a h the case of the cylinder, sum of bonds along CS-X axis, plus radius of outer atom of X (Le., for ‘‘CEN,” sum of ‘‘Ce-c,’’ “C-N,” and radius of nitrogen). For the single atom substituent, the radius of the sphere, center a t Cg, was taken as projection (see footnote b). For the polyatom substituent the “h” of cone (see footnote b ) was taken as the projection length. T h e bond lengths, bond angles, and atomic radii used were based upon values of relevant data obtained from the following sources: (1)“Lange’s Handbook of Chemistry,” 9th ed, Handbook Publishers, Sandusky, Ohio, 1956, p 108; ( 2 ) “Interatomic Distances,” Chem. SOC., Spec. Publ., No. 11 (1958); (3) Y. Yukawa,Ed., “Handbook of Organic Structural Analysis,” W. A. Benjamin, New York, N. Y., 1965, pp 510-525. The volumes are to be considered approximations for two reasons. Firstly, the values for bond lengths and angles are taken from aliphatic and aromatic systems and not from steroidal systems. For example, the bond length of “C&=N” was derived from the values for the related bonds in vinyl cyanide (CH,=CHC=N) and benzonitrile (PhCN). Similarly, for bond angles, the “C6-O-CH3” angle was derived from the related angle in 1,4-dimethoxybenzene. Secondly, volumes were derived by considering all the substituents, excepting CN, as describing a sphere, with center a t c6, and taking one-half the sphere volume ( 4 / 3 ~ r 3 )as the value. The radius ( r ) of the sphere was derived as follows. Single atom substituent from addition of bond length c g to substituent plus atomic radius of substituent. For polyatom substituent, illustrated with methoxyl, values for right triangle [f,e , ib, c, d ) ] obtained using 6-F (35)3 > 6-Br (42)3 > 6-N3 (20) > B-OCH3 ( l 4 ) I 6 > 6-SCN (12) > 6-CF3 (11)15> 6 - C S ( 6 ) ” > 6-CH-YOMe (2)17 > 6-H (1). 6-CHO (1),Ii 6OCzH2 ( I ) ” ” * > 6-OCOCH3 (0.2)**“ > 6-NHCOCH3 (iO.l).ttt We are quite aware that many different parameters ma\ he considered in the correlation of activity with struct ural modification. However, we addressed ourselves t v t w o factors. namely steric and electronic. which we felt may he contributing to modulation of progestational act i v i t y , and we chose to define the steric factor by considering the volume requirements of a 6 substituent and also its distance of extension from C‘S. Table I1 tabulates the progestational activity and steric factors defined by the \lcilume occupied by “X” and by its projection from C g . T h e volume was derived by considering “X” as occupying either a cylinder or one-half of a sphere with the center at C 6 . The projection of “X” from Cg was considered to be along the bond axis from Cg (Table 11, footnote a ) . Although the derived values are qualitative because of the approximation used for calculating the volumes, we consider them sufficiently accurate to illuminate comparative differences.
-
-+
-+
=: Preparation 111 the 16-desmethylene anaiog of 4b from the related G,7-oxld10 in the progestational assay), the 1:olume should be less than 60 A3 b u t greater than the volume requirement f’or hydrogen as “X.” The second was that for those substituents which , CXl. hteric fa(.are strongly cross-conjugated ( i . ~ CHO. tors are relatively unimportant. but electronic factorh fire critically important. For greatest activity it appears that the volume should be approximately 31 f 13 .A3. The most active of the compounds cited has “X” as methyl. High activity in thih case is achieved by a steric effect, with very little, if any. contribution from a n electronic effect, From consideration of volume requirements, one would then predict high activities for halogen (F. Cl) as “X” and this is the casc’; yet. subtle electronic interaction must also be important since their activities are not only less than that for methyl but not equal to each o:her and not proportional to size. One would also expect from a consideration of only the volume factor that trifluoromethyl would have act ivit) approximately that of bromo; yet, it does not. The steric factor would appear to be clearly manifested by the activity differences of methoxy and ethoxy, and the moderate activity of the groups X3 and OCH3 may be rationalized from a consideration ot’ the steric factor, without even evaluating the importance of the electronic factor i n either case. The activity of the S C S group (albeit moderatej would not have been predicted from our volume calculations. Another parameter which may be used in conjunction with volume of the sphere is the circumference of the circle circumscribed by the substituent (Table 11, circuniference column). With the dimension of 4.27-8.67 A one may group the most active substituents-~-F. CI. CH:j. Hr: with the dimension of 11.93-15.64 A may be grouped the motierately active N3. OCH3. SCS. CF,; and with the dimension of 23.68-28.57 .\ may be grouped the least active NCOCHZ, OAc, O E t , and C=XOiCle. This method of calculation fits the bioactivity data better for S C S and CFa than does the volume approach. without diminishing the reliability for calculation of effects of other subst ituenta. An inspection (Table 11) of the influence of the length ot bond projection to activity does not reveal any significant trend(s) but does point up that volume requirement+ arc. more easily related to activity. It remains obscure why there is such a large enhancement in activity derived from change in the substituent from hydrogen t o methyl or halogen. This mag’ suggest an anchoring or fitting dependency of the G substituent with respect to the active site of an enzyme, for example. a :Iketo reductaae or a L 4 reductase (assuming equal aiaiiabilitl- at the site). In any event, tor a set of &substituted progestational structures differing in an)’ way from the 6-dehydro-6-suh stituted 16-methylene-l;n-acetoxyprogesterone. the q i t I mum substituent at the 6 position would need til he determined by experiment but would most likely come t‘rom within the group Me. CI. Br, F, or a nonconjugated stituent which fits into the volume requirement def by this group. &Azido- and 6-Thiocyanatocorticosteroids. In view of the notable adrenal-suppressing effects associated with the administration of la to rats, the 6-azido-6-dehydrocortisone 21-2 state 1 la and 6-azido-6-dehydrocortisol21. acetate 15a were prepared. The synthetic pathway illus trated in Scheme 11. which parallels that employed t o pre pare 6-azido-substituted progestins, was used. Opening ot’ Ga.7ci-oxidocortisone 21-acetatel 8 with azide ion in ;i weakly acid medium afforded the 63-azide 9a in gooti
Journal ofMedicinal Chemistry, 1973, Vol. 16, No. 12
A6-6-SubstitutedProgestational Series
Scheme I1 CH,OAc
CH~OAC II C=O
I
& H :
-
0
----t
0
. ,
‘0 8
“OAc
X
X 9
10 a, X = N,;
‘0
CH,OAc
I
I
-
.,
X11
CH,OAc
I
I c=o
J=JP
0
b, X = SCN
CHzOAc
CH,OAc
0&-OH
I
I c=o
---+
&OH
CH,OAc
CH20Ac
o@-OH
1373
c=o
0 @-OH
12
14
X 15
CH,OAc
I c=o
0&-OH 19 a,
X = N 3 ; b, X = C l ; c , X = H
yield. In the same way, the cortisol analog 1218 gave 13. Table 111. R a t Granuloma Pouch. Acetylation of 9a and 13 with AczO-pyridine yielded the EXUrespective 7a-acetates, loa and 14. Elimination of the 7a date position in 10a and 14 was accomplished with TMAFCompd inhibi- Adrenal Thymus Body Tested CH&N to give the desired corticosteroids lla and 15a, no. tion* atrophy* involb wt at Y respectively. The 6-thiocyanatocorticoid 1 l b was also pre15c Inact Inact Inact No effect 480-120 pared from 8 using the route described for 4b. 16b 0 . 3 0.8 0.7 Gain at high 480-120 As a final demonstration of the versatility of the syndose thetic methodology, 6a,7a-oxido-4-androstene-3,17- 16a 1 . 6 0.8 1.1 No effect 480-120 dione4 (16, Scheme 111) was converted into the 6-azide lla 1.2 c 1.3 Suppression 240-60 Active 18a and 6-thiocyanate 18b. l l b Inact Inact Inact No effect 360-90 Biology of Corticoids. In the given limited corticoste19 0.2 0.2 0.2 960-240 Scheme I11 .See E. J. Collins, J. Aschenbrenner, M. Nakahama, and I. I. A. Tabachnick, Proc. Int. Congr. Horm. Steroids, 2nd, 530 (19661, for the method of assay. *Relative potency with the stand ird, prednisolone acetate, assigned activity of 1. cPotency ( ould not be calculated because of nonparallel slopes. 0
M+ ‘0
16 0
0
0
dp0@ a,
X
x
17
18
X = N,; b, X = SCN; R = H or CHBSO,
roid series, it seems that somewhat different considerations govern activity enhancement achieved through 6 substitution than prevailed with the progestins. Thus, the 6-azido-6-dehydro moiety potentiates (Table 111) by all indices significantly better than the 6-chloro-6-dehydro moiety, the former being 4-8 times as active as cortisol 21acetate 19 and the latterla 1,5-4 times as active. Thiocyanate substitution, on the other hand, provides no measurable activity enhancement in contrast with observations in the progestin series. There are as yet insufficient data to reach conclusions other than t h a t the 6-azido-AG system offers interesting possibilities for activity-enhance-
1 3 i 1 Journai o j M e d i c i n a i Chernistri,. 1973. Voi. 16. N o . 12
Table IV
Hun
a
b c
A m t of S o l v e n t , DDQ. 4a. mg ml mg 102 507 1000
8 30 50
60 320 640
Yield of prodTime, Temp. uct. min 'C mg
30 45 60
80 80 80
57 235 650
ment of corticosteroids. These possibilities will he explored in subsequent publications.
Experimental Section Gd- Azido- 16-methylene-iit. litu-dihvdroxy-l-pree;nene-:1.20dione li-Acetate (2a). T o 3 solution of 6 . 7 ~ - o x i d o1 ( 4 g) in MeOH (700 mli and AcOH (4 mli was added a solution of N a S 3 (8 g i in 240 ml of' water. The mixture was allowed to remain at room temperature for 94 hr. then diluted with water, and extracted with CHC13. Evaporation of the solvent and trituration of the residue with ether afforded 3.6 g of 2a. Crystallization (EtOAci 238 nm gave the analytical sample: m p 229" dec; ["ID -92.2": ,,,A, i r 13.155); An,:,x 4.75 p : nmr 3.74 ibr. :-HI, 4.10 id, J = 2.75 Hz. 6-Hi. and 5.93 (4-Hi. Anui. (C24H3105N31 H. N;C: calcd. 65.28: found. 64.82. 63-Azido- 16-methvlene-in. l'in-dihydroxv-l-pregnenene-:~,2~)dione 7,17-Diacetate (3a, R = CHBCO). A. From 2a. A mixture of 300 mg of 2a. 0.6 ml of Ac20. and 4 ml of pyridine was allowed to stand at room temperature overnight. After addition to water. collection of the resulting insolubles. and crystallization from XIeOH. the analytical sample (210 mgi was obtained: m p 198" dec: [ ( t ] r i -113.3': A,,, 2333 nm ii 12.000): nmr 2.05. 2.08 i 7 - and 17OCOCH3j. 4.14 id. J = 3 Hz. &HI. 4.85 id. J = 2.5 Hz. ;-HI Anal. iC26H3306K3i C , H, S . 13, From 6 ( R = H). The 6d-azido-7~\-hydroxyt i 1100 mg) way dissolved in a solution of AcOH (2.,5 ml). TFAA i l . 2 5 mli. and pTSA-H20 i? et f'ected hy thick-layer chromatography i silica yei. ('HCI:I ~ E :O t A-. 9:1! tci give 1.1 g of la which was crystallized trcini ZleOH. ,Ittiirtl iCHC!Si 4.75. .5.7i 1.15 i li)-CHs), 2.06 (17-OVOC'H:5~ i d .I = 1.; H z ) . i j 1'; i J - f L !nu; (:la).A -uspension of T51AF-5Hz0 ( 2 pi i n CH3CX (200 m l ) was heated with stirring until the scilid li quified. Atter cooling under K z ( g ) to ambient temperature. 2 :: (11 3a ( R = CHsCO) aah added and the reaction mixture stirred ii! room temperature tor 3 hr. The wlvent was evaporated under S2igj in ~ ' n c u oto about 100 ml. and then the mixture wah addeti to water and extracted with CH2CI2. After wirk-up, the re5iduz was trituated with boiling ether 125 mll. cooled t o - 2 0 " . anti f i l tered toohtain 1.11 g o f l a i 6 3 . 5 7 ~ 1 C . From :la i R = CH3S02) ,with 1)JlF. 'I'(i a suhpenbiiiri t i t TMAF (f'rom 200 nig of TZIAF- 5H20 by evaporation three tiin+ of 150-ml portions of CH,CNI in IIh3F was added 100 mg of 7~ mesylate 3a. After remaining at room temperature for 111 hr. t i c indicated complete transformation [ i f starting material. The reaction mixture was added to water i l 7 3 mll. S a C l i 5 yr uas added. and the insolublw were collected ti! tiltration. The filtrate u-a.; extracted with CHZCl:! and the residue from the CH2CIz evaporation was cornhined with the collected precipitate. PreparatiIe s i l i afforded 130 mg (37.57~) oi l a . cii pel tic (CHCl:,--EtOAc. I). From :la iR = VHsSO1) with TJIXCI. Mesylate :la I l:, and E P Olireto J M e d P h a r m C h p m 5 . 975 (1962) 111)J Hakami. 5 Ono. and A Kali Ruii C h c m 4 o i J a j i I t . 1628 ( h i ) . ( 1 2 ) E. I,. Shauiro. T. I,. Pouuer. L. CVeber. K. S e n . and H . I-. Herzog. J . :Wed. C h e m . iZ; 631 i1969). (13) K . Ponsold and G. Schubert. Z. ( ' h e m , 8 , 465 (1968): ('h(zrn ;Ibstr.. 70, 45682j (1969). (14)L. S. Luskin. G . E. Gantert. and W,E. Craig. .I A m w Chem Soc.. i s , 4965 (1956). (15) H . P. Faro. R. E. Youngstrorn. T. L. Popper. H. S e n . .inti H. L. Herzop.J. M e d . C h c m , 15,679 (1972)). (16) R. Rausser and H. Tiberi. t7,S. Patent 3,629.302 ( I k c 21. 19711, 1 1 7 1 7'.L. Popper. H. P . Faro. F. E. Carlon. and H . L. Herzog. ./ LVed. Chem.. 15, 555 (197%). (18) British Patent 951,460 (hlarch 4. 19641: ('hc~m .2h\lr, f i l . 5 7 3 3 ~( 19641.
N-Alkylnorketobemidones with Strong Agonist and Weak Antagonist Properties 'rokuro Oh-ishit and Everette L. May* Lahoraton. of Chemistn, AVationalInstitute of Arthritis, Metabolism, and Digestice Diseases, .Vational Institutes of H e a l t h , Hethehda, Ma>land 20014. Received Jul?, 2, 1973 Replacement ot' the .V:-methyl group of' ketobemidone ( 1) with propyl, cyclopropylmethyl, or allyl [ t i . 6. 11, and 13) does not produce antagonists but weak to medium strength analgesics with high physical dependence capacity [Rhesus monkeys). When the N-substituent is amyl ( 8 ) strong analgesic and atypical properties of antagonism are exhibited. ,V-HexyI- and -heptylnorketobemidones (9 and 10) are between morphine and pethidine in analgesic potency. and both are weak, long-acting, nalorphine-like antagonists in monkey and guinea-pig ileum experiments. LV-Ethylnorketobemidone( 5 ) is a weak agonist: but the .\'-butyl homolog 7 is as potent as morphine with low physical dependence capacity. 0H It is well known t h a t strong analgesics of fused tricyclic OR OH to hexacyclic systems (benzomorphans to endo-ethenooriI pavines) can be converted t o potent antagonists by replacement of methyl on the nitrogen with allyl. propyl. or OEt cyclopropylmethyl. More recently it was demonstrated I I i/, t h a t the strong analgesic, 5-m-hydroxyphenyl-2-methylN morphan.' bicyclic in character, gave only weak antagoI s nists by this simple change despite a favorable location of VH K R the phenolic hydroxyl. We now wish to report complete 1. R = H;R,= Me 4,R=H E,R = CHOHEt failure to obtain antagonists from the powerful analgesic, 2. R = R~= Me 5 . R = E t 13. K = COEt ketobemidone (monocyclic), with these three S-substitu3.R = Me: R, =H 6. R = Pr tions and the preparation of strong analgesics containing properties of antagonism by higher N-alkyl substitution. 7.R=Hu Chemistry. The starting material, 2 , for the prepara8. R = Am tions described herein was obtained in double the yield 9. R = Hex and one-fifteenth the time reported by Avison, e t ai..' in 10. R = Hept the reaction of EtMgI with 4-cyano-4-m-methoxyphenyl1 -methylpiperidine, simply by very efficient stirring. Con11. R =allyl version of 2 to 3 was effected by the ethyl chloroformate Pharmacology. In Table I are given analgesic activities method .3 (hot-plate and Nilsen),5 physical dependence capacities Reaction of 3.HC1 with alkyl bromides or iodides in (PDC),6 and properties of narcotic antagonism for ketoboiling ?-butanone or DMF a t 90" (KzC03) followed by bemidone ( 1 ) and pentazocine (standards) and analogs o f treatment of the resultant ,\'-alkyl methyl ethers with 1. Predictably, a change from methyl t o ethyl with respect boiling 48% HBr gave phenols 5-10. Compound 11 was to the N-substituent ( 1 L'S. 5 ) nearly abolishes the CNS similarly obtained using allyl bromide. effects seen in the strongly active 1, partially restored in The cyclopropylmethyl analog, 13, was synthesized by a t h e N-propyl homolog 6 and its 0-acetyl derivative. Nless direct route. Phenol 4 , prepared from 3 with boiling Butyl homolog 4 is half as potent (as an analgesic) as 1 48% HRr, and cyclopropylcarbonyl chloride gave the O,,V but is more toxic and has little PDC. The N-amyl derivadiacyl derivative which was reduced to carbinol 12 with tive 8 is nearly three times stronger t h a n 1 but will not I,iAII&. Oxidation of 12 to 13 was effected with DMSOsustain morphine dependence in monkeys; in fact, it disAc2O.i or by the Oppenauer method. plays some (atypical) properties of antagonism. The hexyl and heptyl homologs 9 and 10 are typical nalorphine-like t \':siring Associate irom Tokyo. .Japan. On lea\e from Tanabe Seiyaku antagonists with a longer duration of action, a steeper ( ~ mI,td. , Saitama, J a p a n .
4
