mol) of p-TosC1 in 35 ml of pyridine. Stirring was continued for
`0.5 hr aft,er which the solvent was removed by distillation. The
`residue was partitioned between H20 and EtsO. The Et20
`layer crystallized to give 3.8 g of 12. Evaporat,ion of the mother
`liquor gave 3.5 g of mixture 13 which was not, charact,erized.
`Two recrystallizations of 12 from Et,OH afforded material which
`had mp 172-174". 9nal. (C22H29N03S) C, H, N.
`cis-1,2,3,4,4a,5,10,lOa-Octahydro-5,5-dimethyl-l-( p-toluene-
`12 (2.8 g,
`sulfonyl)benzo[g] quinoline (14). A.-Compound
`0.07 mol) was cyclized according to the procedure given above for
`the preparation of 9 and 10. Crystallization of the crude residue
`from EtOH gave 2.2 g of 14. Recrystallization from EtOH gave
`ilnal. (Cp2H2iSO2S) C, H, N.
`material, mp 143-145".
`B.-Residue 13 (0.54 g, 0.0014 mol) was cyclized according to
`t'he above procedure to give 0.36 g of 14 identical wit,h that
`prepared above.
`derivatives were
`Carbinols for Cyclization Studies.-These
`prepared from the pure isomeric amino alcohols 8b.2 Reductive
`met,hylatioii with CH20 and H, over Pd-C gave the S M e deriva-
`tives: cis isomer m p94-96", Anal. (CliH27NO) C, H, N; trans
`isomer mp 78-79", Anal. (CnH27NO) C, H, 3. Acylation with
`-4cC1 or p-08C6HaSO~Cl in CHC13 in t,he presence of Et3N gave
`the correspoudiiig amide: cis-S-acetyl, mp 138-141 ", Anal.
`(C18H27?jO3) C, H, S ; trans-S-acetyl, mp 111-113°, Anal.
`(ClsH2,N03) c, H, N; CiS-Av-p-02SC&xOy, mp 182-186",
`Anal. (C22H?6N2O6S) c, H, ?j; trUnS-p-O&C&KOz, mp 132-134",
`Anal. (C22H28S206S) C, H, N. The p-CgHlN02 derivatives were
`prepared according to the procedure of Badar, et al.13 These
`compounds could iiot be obtained crystalline, axid were char-
`acterized only by t8heir ir spect,ra.
`3-Isopropylidene-2-p-methoxybenzylpiperidine and Derivatives.
`-The
`neutral fraction from the decarboberizoxylation of 1-
`benzyloxycarbonyl-2-( p-methoxybenzy1)-a,a- dimethyl- 3 -piperi-
`dinemethanol was allowed to stand for 3 mont,hs. A 21.7-g
`sample of this residue was diluted to 200 ml t,otal volume with
`EtOH and hydrogenated over Pd-C at room temperature and
`4 atm. Uptake ceased after 3 hr withthe consumption of ap-
`(13) H. Bader, .I. R. Hansen, and F. J. JIcCarty, J . Org. Chem., 31, 2319
`(1966).
`
`Journal of .Iledicinal Chemistry, 2910, 5'01. 12, S o . 3 525
`
`proximately 1 molar equiv of H2. The basic fraction was dissolved
`in dil HCI arid cooled to give, after filtration and drying, 9.1 g of
`crude 23, HC1. Recryst,allizatioii from EtOH-Et2O gave pure
`23, mp 25.i-257", iimr (CDCL, TMS) 413 (AzB2,4) 223 (a, 3 ) ,
`95 (s, 3), 64 HZ (s, 3). 9nal. (C16H2rC1xO) C, H, IV.
`The XRIe and p-S02C6H4NOn derivat,ives were prepared by the
`procedures indicated in t,he previous sect,ioii aiid had the follow-
`ing properties: XlIe.HC1, mp 179-183", Anal. ( C I ~ H ~ ~ C ~ N O )
`C, H, N; Lv-p-SO&sHaNOr, nip 114-116", Anal. (C2~H26K20jS)
`C, H, N.
`corre-
`Benzo[y] quinoline Derivatives as Nmr References.-The
`sponding derivatives of cis- and trans-1,2,3,4,4a,5,lO,lOa-octa-
`hydro-5,5-dimethyl-7-methoxy-benzo[g]quinolirie were prepared
`by the same procedures and the iimr spect.ra recorded. The com-
`poiiiids not, previously reported had t,he following physical proper-
`ties (the numbers in pareiit,heses following the melt,iiig point are
`t8he chemical shifts in Hz of the gern-Mez groups in the 60 3IHz
`iimr spectra): cis-N-p-C6H4?1T02, glass (80,791, Anal. (C22HlS-
`N203) C, calcd, H, 6.89, N, 7.67; foniid, H, 7.41, X, 8.60; trans-
`(83,70), Anal. (C22H2&203) C, H,
`N-p-C6H1NO?, mp 164-166'
`calcd, N, 7.67; found, 9.04; cis-.Y-acetyl, nip 81-85'
`(80,78),
`dnal. (ClsH2;N02) C, H, calcd, S , 4.87; found 5.33; trans-JY-
`acetyl, mp 157-159' (80,68), Anal. (CISH2;NOI) C, H, 5 ; cis-N-
`p-SOsC6HaN02, mp 159-161 O (81,79), Anal. (CSUH~,NZO;S) C, H,
`N, trans-N-p-S02C6Ha302, mp 204-205'
`(79,.39), Anal. (cZ~H26-
`SzOjS) C, H, S.
`solutioii of 100 ml of AcOH atid 20
`Cyclization Procedure.-A
`ml of HyS04 was used for all cyclizations. A 125-mg sample of
`the carbinol and 1.0 ml of the acid were heated on a steam bath
`for 5 min, diluted with 25 ml of H20, made slightly basic with
`KH4OH, and extracted with 25 ml of CHC1,. The extract was
`dried, filtered, and concentrated and the entire residue wed for
`nmr. The resulting spectrum was compared with that of the
`two pure products, and the relative amounts of each determined.
`Acknowledgments.-The
`authors wish to thank Mr.
`I<. D. Fleischer for elemental analyses, Dr. R. I<.
`Kullnig for spect'ral data, and Nr. A. Ii. Pierson for
`pharmacological results.
`
`Novel Analgetics and Molecular Rearrangements in the
`Morphine-Thebaine Group. XVIII.'
`3-Deoxy-6,14-endo-etheno-6,7,8,14-tetrahydrooripavines
`
`JOHN \Ti. LEWIS AND nIlCH.4EL J. K E A D H E l i D
`Pharmaceutical Research Laboratories, Reckitt ck Sons, Hull, England
`
`Received Yovember 10, 1969
`
`7-Subst,it,uted 3-deoxy-6,14-endo-ethetio-6,7,8,14-tet~rahydrooripaviiies have beeii prepared by hydrogeiiolysia
`
`of the oripavine diethylphosphatyl esters.
`In some cases part'ial reductioii of the etheno bridge also occurs.
`The deoxy compounds show arialgetic pot.ericy intermediat,e between the oripavine and thebaine analogs.
`
`The nature of the CS substituent' is very important in
`determining analgetic potency in the morphine series
`(1).2 Thus heroin (IC) is more potent' than morphine
`(la) which is itself considerably more potent than co-
`deine (lb). In the related series of analgetics (3b-6b)
`derived from 6,14-endo-ethenotetrahydrooripavine the
`effect of removing the phenolic hydroxyl group by
`hydrogenolysis with K a in liquid IYH3 of the diethyl
`phosphate derivatives (2) a has now been investigated.
`The phosphates were prepared by reaction of thr
`oripavine derivatives with diethyl phosphite and CC1,
`and were dissolved in E t 2 0 for the Na-liquid NH, re-
`
`(1) Part ST'II: J. IT. Leais and W. I. Rushworth, .J. Chem. Sac. C,
`560 (1970).
`(2) N. El. Eddy. H. Halhach, and 0. J. Braenden, Bull. W . H . O . , 17,
`569 (1957).
`(3) G. \V. lienner and h-. R. LTXliarns, J . Chem. Sac.. 522 (1965).
`
`action. In most cases the hydrogenolysis reaction went
`to completion but purification of the products was not
`always easy.
`In the case of the 7-dimethglcarbinol
`( 3 ~ ) a by-product having similar chemical and physical
`properties was isolated by preparative tlc. This was
`ahown to be identical TTith the 3-deoxy compound ( 8 ~ )
`derived from the 6,14-enclo-ethanooripavine (8b). Hy-
`drogenation of the olefinic bond by S a in liquid S H j
`was surprising in view of the fact that 3a is catalytically
`hydrogenated only with diffi~ulty,~ and reduction of
`disubstituted olefins by metal-amine systems occurs
`only with the powerful Li-alkylamine reagents.j The
`
`(4) I<. 11.. Eentley, 12. G. Hardy, and 13, Meek, J . Arne,.. Chem. Sac., 89,
`3273 (1967).
`( 5 ) Herschel Smith, "Organic Reactions in Liiiuid
`science, 1963, p 213.
`
`. h m o n i a . " Inter-
`
`Page 1
`
`RB Ex. 2005
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`
`p l i e i i ~ lmetliyl carbinol 6c alw underwent partial
`11) drogeriation of the etheno bridge when the phosphate
`estrr was hydrogenolyzed. Surprisingly the C7 ethyl
`derivative 15c having a more accessible etheno bridge
`did not suffer partial hydrogenation.
`Oripavines lob-14b in which the S-substituent i i
`:illy1 or cyclopropylmethyl were converted into 3-
`d w x y compounds without affecting the S-substituent
`but tlir rtheno bridge in 12c underwent partial Iiy-
`drogenat ion.
`
`\
`R'
`2
`
`1
`
`a, R l = R ' = H
`b. R1 = Me; R? = H
`c, R1=R2=AAc
`
`I shov s the
`Structure-Activity Relationships.-Table
`analgetic and morphine-antagonist potencies of the
`deoxy compounds compared \\ ith the corresponding
`
`HO-k-(
`bkjw
`8. RL = Me
`9, R- = CPM'
`
`HO-
`
`;.- --Me
`I
`R-
`3 1%- =.\le
`4, R- = 1'1.
`5. R - = ~ - P e l i t j l
`6. R' = I'h
`7. R-= Phenethyl
`
`I Et
`15
`
`HO - 6 ---Me
`
`10. K- = Me, R'=aliyl
`11, R- = n-Pr. R 3 = allbl
`12. R- = Me; RJ = CPM
`13 R2 = Et, R' = CPM
`14. RL= /so-Pentyl, R' = CPM
`a, R1 = OMe
`b. Rl =OH
`c, R1 = H
`"rPM = cyclopropylmethyl
`mtlt l i ~ . l oripavirie. :tro niorphine mtagoriists t lie dtArivtd
`droxy compuunds dion- much weaker antagonist
`, pronounced analgrtic
`character :ind, iti tilost e:
`activity. O i l tlic other Iiand tlir potency of tlir X-
`yubstituted oripavirie analgetics i., considerably great ('IS
`
`Page 2
`
`

`
`CNS-STIMUL.\TORY S IKTHONIX
`
`Journal of Medicinal Chemistry, 1970, Vol. 13, .Yo. ,7 527
`
`than that of the deoxy derivatives. The corresponding
`thebaine derivatives have profiles similar to the deoxy
`compounds but with less analgetic character.
`
`Experimental Section
`Melting points were determined on a Kofler hot-plate and are
`uncorrected. Where analyses are indicated only by symbols of
`the elements the results obtained for those elements were within
`&0.4% of the theoretical values. The structures of all compounds
`were assigned on the basis of compatible ir and nmr spect,ra.
`See Table I1 for experimental data.
`6,14-endo-Etheno-7~-ethyltetrahydrooripavine 30-Diethyl
`( 5 ml) was added slowly with vigorous shaking
`Phosphate.-EtrN
`to an ice-cold mixture of 6,14-endo-etheno-7a-ethyltetrahydro-
`oripavine6 (10.8 g), CCI, (10 ml), and diethyl phosphite (4.5 ml).
`The mixture was set aside at room temperature for 18 hr. The
`mixture was diluted with HVO and the organic layer separated.
`The aqueous solution was extracted with CHCl,. The combined
`organic3 soliitiorrs were washed several times with 1 i\’ NaOH and
`finally HzO. The dried (Na2S04) extraat was evaporated and the
`residue recrystallized (C6H6-petroleum ether) to give 7.0 g (47%)
`of the phosphate, mp 135-137’. Anal. (CLB&NO,P) C, H, N.
`(6) K. W, Bentley, D. G . Hardy, J. W. Lewis, M. J. Readhead, and A’. I.
`Rushworth, J . Chem. Soc. C, 826 (1969).
`
`The phosphates of the other oripavine derivatives’ were prepared
`by arialogous procedures and were hydrogenolyzed without
`purification.
`General Procedure for the Hydrogenolysis of the Oripavine
`Phosphates.-The
`crude phosphate was dissolved in E t 2 0 and NHr
`was added (20 ml/g of phosphate); to the mixture Na ( 2 g-atoms)
`was added in small pieces, as rapidly as frothing would allow.
`EtOH (2 mol) was then added and the NH8 allowed to evaporate.
`The residue was treated with H 2 0 and extracted with Et2O. The
`combined ethereal extracts were dried (NazSO,) and evaporated.
`Crystallization of the residue gave the 3-deoxyoripavine.
`Biological Methods.-Analgetic
`activity was determined sub-
`cutaneously in the rat tail pressure test of Green and Young8 and
`morphine antagonism by the method of Green, Ruffell, and
`W a1 ton. 9
`
`authors thank N r . hIichael
`Acknowledgments.-The
`Smith for assistance with synthesis, A h . Cyril Young
`for preparative tlc, and Dr. Alan L. A. Boura for the
`pharmacological results.
`
`(7) K. W. Rentley and D. G . Hardy, J . Amer. Chem. Soc., 89,3281 (1967).
`(8) A. F. Green and P. A. Young, Brit. J . Pharmaeol. Chemother., 6 , 572
`(1951).
`(9) A. F. Green, G. K. Ruffell, and E. A’alton, J . Pharm. PharmacoL, 6 ,
`390 (1954).
`
`Central Nervous System Stimulants of the Xanthone Group
`
`P. DA RE, L. SAGRAMORA, V. XAKCINI, P. VALENTI, AND L. CIMA
`Department of Chemistry, University of Pisa, Pisa, and Department of Pharmacology,
`University of Padua, Padua, Italy
`
`Received October 17, 1969
`
`A series of basic derivatives of methoxy-, hydroxy-, and chloroxanthones were synthesized and tested pharma-
`Some N-disubstituted 4-aminomethyl-3-methoxyxanthones show a powerful CNS stimulating
`cologically.
`activity. Structure-activity relationships have been examined.
`
`I n continuation of our r e s e a r c h e ~ ’ ~ ~ ~ ~ on CKS
`
`stimulating drugs of the benzopyrone series, the most
`significant of which is 3-methyl-7-methoxy-8-dimethyl-
`aminomethylflavone (dimefline, I), the xanthone analogs
`I1 have now been synthesized.
`
`CH:O &E:5 \
`
`&OCH:
`
`I CHJJR?
`I1
`This modification of structure I was an outcome of
`our previous work and was made with the purpose of
`devising a drug which would reduce some undesirable
`side effects (such as the excitatory cortical component
`of the analeptic activity) as well as the toxicity and
`at the same time improve the clinical safety. The nelv
`carrier moiety of the CHzNRp group was to permit a
`better insight into the structure-activity relationships
`and to make use of synthetic methods such as addition
`reactions and partial or total reduction of the CO group,
`which are more difficult to perform with chromone or
`flavone analogs.
`
`(1) P. D a Re, L. Verlicchi, I. Setnikar, W. Murmann, and M. J. Magis-
`tretti, Nature, 184, 362 (1959).
`(2) I. Setnikar, W. Murrnann, M. J. Magistretti, P. D a Re, and L.
`Verlicchi, J . M e d . Pharm. Chem., 8, 471 (1961).
`(3) P. D a Re, G . Bonola, and L. Verlicchi, J . Med. Chem., 7, 162 (1964).
`
`The present work concerns some N-disubstituted
`4-aminomethyl derivatives of 3-methoxyxanthone1
`selected on the basis of previous results2 in the benzo-y-
`pyrone series, as well as the corresponding derivatives
`of 3-methoxy-6-chloroxanthone, which were prepared
`in order to take advantage of the possible widening of
`the safety margin induced by the introduction of
`CIS4 Furthermore, owing to the symmetry of the xan-
`thone molecule we had the opportunity to prepare the
`bis(aminomethy1) derivatives of 3,6-dihydroxy- and
`3,6-dimethoxyxanthone and so to verify the so-called
`molecular doubling principle,j by which one could
`expect an inversion of the previously observed activity.
`A few papers concerning the same subject (prepara-
`tion of SIannich bases of hydroxyxanthones and alkyl-
`ated xanthones) have appeared,6r7,8 but no biological
`data have been reported. These compounds however,
`on the basis of our previous findings,2 ought to be less
`active than the AIeO analogs.
`We also wish to report an attempt to apply the
`
`(4) A. Burger, “Medicinal Chemistry,” 2nd ed., Interscience Publishers
`Inc., New York, N. Y.. 1960, p 43.
`(5) A. Lespagnol, ActuaZ. PkarmacoZ.. 6, 115 (1953).
`( 6 ) A. Mustafa, M. M. Sidky, and F. hl. Soliman, Can. J . Chem., 41,
`1731 (1963).
`(7) Y. S. Agasimundin and S. Rajagopal, J . Indian Chem. Soc., 41, 471
`(1964).
`(8) C. S. angadiyavar, Y. S. Agasimundin, and S. Rajagopal, J . Karnatak
`Unau., 11, 52 (1966).
`
`Page 3