Triptycene Derivatives as Medicinal Agents
The reactioii of beiizyne with 0-substituted aiit,hrac.eiiesyielded rt series of trip1yi:eiie derivatives, ivhic.11 were converted t,o a variety of driig-related structures containing triptyceiie as t,he :i,rornatic blockiiig group. Several of the new compound3 are active as antiinflammatory agelit-.
During the recwit developiiiciit of iiiediciiial cheiiiistry, drugs with widely varied clinical application havc cmierged, arid a large nuiiiber of these niay be portrayed by the gross structural arrangenient I.
p z q r"J d k ? 1 chaiii
basit
flulctloll
biockiiig group
1
I'or soiiie time evidence has accuiiiulatedl supporting the idea i liat niaxiniurii biological act ivitp results only whcn the blocking group i s planar. However, the rccwtt advent of c.linically uwful driigh TI i t l i bciit or skewed aroinatic nioieties, i . ~itiiipraiiiiiie2and amitript y l i n ~ ,cdc., ~ has refocussed attciitioii 011 thc sterir rcquireiiic~ittsof the blorkirig group. K i t h this i n iiiir~d i t was of iritcrcst to c~xamitic diugs roiitaiiiitig t h e highly symiiietrical. aroiuatir. tml noiiplanar t ripij-( ~ ~ i blocking c : fimctioii (11) T h o prc srribcs the preparation aiid phariiiarolo
n.
v
.\ I
-T
~
K
0 I11
,nepropioiiatcx \\-us tli(, 3 i a i . I i t i g iiiaterial for elaboration of the 2-! 3 - , arid 4-carboii si&% ned in Chart I (T = 9-triptyvyl). of t riptycenealdehyde provided :t 'y into the single-carbon sidwhairi group as suniniarizeci in Chart 11. Triptyceriealdchyde (8) \\-as rmdilp available by liydrolysis of the acrtal 7, aiid oxidaiiori of ihe aldehyde t o iriptycriiv\ I Jtilrs ancl 11. f ; ll~!l?r, ./. . I m . C'hcrn. Snr:., 82, :48(l2 I,. Fririlmari a n d I:, Immillo, I h i d . . 85, 1.519 (1'363).
,
l ! t ~ i ~ l l .
TRIPTYCENE DERIVATIVES
May 1965
343
CHARTI T-CHzCH&OOCH,
CHARTI11
NaOH __.+
T-CH~CHZCOOH
33
T-CH2CH2COCI 34
T-CH2CH2COXH2
T-CH,CH&OCl
34
35
1
T-CH&H,COSHII 35, 37, 39, 41, 43
T-CH2CH2SHCOOCHs
1
27 NaOH
1
1
or Li.ilH4
T-CH&H&O(CHz)rCOOH 51
50
-
(COCl),
HzNNH2
KOH
T-(CH?)iCOOH
acid chloride
-
LiAlHd
4 HCOOH
CHlO
T-CH?CH,SI CH,),
T-CH,CH2CH&( CH3)z
-
40
T-CH~CH~CH~OTOS 46
4
T-(CHz) ,CO(CH2),COOH
T-(CH2)7CONHl
55
53
i
LiAlHd HCI
3 steps
TosCl
45
OH-
36, 38, 42, 44
1 HCOOH 31
a-
HCL
T-CH2CHzCH2XHR
T-CH~CHQKHR 28, 30 CHlO
RKHz
T- CHzCHzCO
EtjN
+
NaCN
T-(CH2) I~CONH,
T-(CHi)xNHyHCI
56
54
Li A 1HI
T-CHaCH&H?CH,NH,. HC149
T-CH,CHCCH?CN
LiAlH41 HCI
CHARTI1
T - ( C H L ) I ~ ~ " I * H C I T-(CH,)j,NHpHCl 57
SOClZ
1
T-COCI
1
IHzNOH
T-CH=NOH 9
LiAlH4
T-CHzNHCHa 14
FrcooIi T-CHJ( CH,)? 16
(
T-SCO
T-COOCHs
\cl
48
T-CX
carboxylic acid (17) was accomplished in excellent yield ueing potassium permanganate in pyridine. This route to the acid seems more convenient than previous iiiet hods. The 8-carbon side-chain series (Chart 111) was made available by acylation of the niorpholine enamine of cyclopentanone with the acid chloride of triptycenepropionic acid (34).lo Repetition of the enamine procedure on the octanoic acid 52 lengthened the side chain to 13 carbons (Chart 111). The amide 56 so formed was transformed to the tridecylamine 57 and by Hofmann degradation to the dodecylamine. 58. Properties of the triptycene derivatives prepared in the present work are sunimarized in Table 11. Pharmacological Evaluation.-The triptycene derivatives were screened in normal mice. Groups of (IO) S. Hunig and \V. Lendle, Ber., 93, 918 (1960).
58
mice were given graded i.p. doses of the various compounds; gross behavioral effects were observed, and comparison was made with known drugs. The bridgehead amines 2 and 3 were C S S depressants, while the 1-carbon side-chain amines 12, 13, and 14 showed a mixed C S S stimulant and depressant activity. The longer chain amines were characterized mainly as weak C S S depressants. On the whole the series was lacking in C S S activity of an interesting magnitude. I:rom these results we ~ o u l dconclude that triptycene does not function as a very effective aromatic blocking group in CNS-type drugs. The evidence from this series seems to support the idea that gross planarity of the blocking group is important. With these results as background, the new coinpounds were then screened in the carragenin-inflamed rat paw antiinflanirnatory test.11 At a dose of 50 nig.ikg. given subcutaneously, the extent of inhibition of inflaniniatioii as recorded in Table I1 was observed. It may be noted that: (1) triptyceiies lacking a basic side chain are devoid of significant activity, ( 2 ) bridgehead amines 2 and 3 are also inactive, and ( 3 ) best activity is observed with side chains containing two or more carbon atoms. Further testing has indicated rather low oral activity for the series. Experimental12 9-Substituted Anthracenes.-The 9-nitroanthracene arid ailthracene-9-carboxaldehyde were commercial samples. The aldehyde was converted to the dimethyl acetal using methanol13 and to the ethylene acetal by means of ethylene glycol.14 The S-cyanoanthracene was made from the aldehyde.1s 9-p-Chloro(11) C. A . Winter, E. A . Risley, and G. W. SUSS, Proc. SOC.Ezptl. B i d . Med.. 111,544 (1962). (12) All melting points are corrected. Infrared, ultrariolet, and n.m.r. spectra n e r e obtained on moat of t h e compounds reported and were consistent a i t h the structures indicated. (13) J . S. Meek and J. R. Dann, J . Org. Chem., 2 1 , 968 (1956). (14) G. Rio and B. Sillion, Conipt. T e n d . , 2 4 4 , 626 (1957). (15) L. F. Fieser and J. L. Hartwell, J . A m . Chem. Soc., 60, 2555 (1938): J. S. Meek and J. W.Roae, ibid., 77, 6 6 7 i (1853).
5 !I1 .-I
TI
345
TRIPTYCENE DERIVATIVES
May 1965
TABLEI1 (Continued) No.
R
a1 p ,
oc.
---n,%-
---c,%--. Solr-enta
Formula
Calcd.
Found
Calcd.
Found
~ i c ~
---N,%--Calcd.
Found
inhibit.
60 3 . 3 5 3.05 80.44 79.66 7 . 7 1 7.76 CzsHaiN. HC1 233-235 NE 54 (CHz)sNHz.HCl OE C33H3603 82.46 82.20 7 . 5 5 7 . 5 8 ... ... ... 55 (CHz).rCO(CHz)4153-154 COOH BS C33H34NO ... ... ... , , , 3.01 2.82 .. 56 ( CHz)izCONH? 117-121 hlE C33H41x 'HC1 7 . 2 6 ~ 7.20 . .. , , , 2 . 8 6 2 . 8 3 34/20 160-162 57 (CHz)13KHz.HCl 7.4% 7 . 3 8 ... ... 2.95 2.91 32/20 58 (CHAzXH2.HCl 163-165 XE CI2Hx9N. HC1 a A = acetic acid, B = benzene, C = acetone, D = dimethylformamide, E = ether, F = ethylene dicliloride, G = methylene chloride, L = ligroin, XI = methanol, S = ethanol, 0 = toluene, P = petroleum ether, S = Methyl Cellosolve, T = ethyl acetate, W = water. Antiinflammatory assay." 0 C1 analysis, d Ad 1-adamantyl. * V = homoveratryl. f S analysis.
.
5
taneously during 6 hr. from separate dropping funnels solutions of 73.5 g. of anthranilic acid in 2450 ml. of dioxane and 78.3 g. of amyl nitrite in 2450 ml. of dioxane. The mixture was refluxed for another 30 min., after which time the solvent was distilled in uacuo. The product was crystallized from methanol; yield (two crops) 85.5 g. 9-(8-Carboxyethy1)triptycene (33).-The methyl ester ( 5 g.) in 85 ml. of methanol was hydrolyzed using 2.2 g. of NaOH and 17 ml. of water during a reflux period of 2 hr. The methanol was distilled in vacuo, and the residue was dissolved in water. The product was precipitated by acidification with HC1. The acid waR filtered and washed thoroughly with water; yield 4.8 g. Acid Chloride of 9-(8-Carboxyethp1)triptycene (34).-A solution of the acid (21.2 8.) in 300 ml. of dry benzene and 16.76 ml. of oxalyl chloride was refluxed and stirred for 1 hr. The mixture was concentrated in uucuo, and the crude acid chloride was recrystallized from a mixture of toluene and petroleum ether (b.p. 60-68')z0; yield 16.3 g. (73%). Amides of Triptycenepropionic Acid.-These were made either from the methyl ester (32) or from the acid chloride (34). The following two procedures are illustrative. Triptycene-9-propionamide (35).-A solution of 9-( @-carbomethoxyethy1)triptycene (5.0 g.) in 50 ml. of methanol and 100 ml. of liquid ammonia was heated for 18 hr. a t 100' in a sealed vessel. The mixture was evaporated t o dryness, and the crude product was crystallized from aqueous methanol; yield 3.92 g. (82%). The methylamide (37) and the dimethylamide (39) were also prepared by this procedure; yields 86 and 60%l,, respectively. 9-( p-Homoveratry1carbamoylethyl)triptycene (43).-A solution of 4.56 g. of homoveratrylamine in 25 ml. of dry benzene was added to a solution of 3.4 g. of the acid chloride of 9-(p6.50 ._ . carboxyethy1)triptycenein 25 ml. of benzene. The mixture was Anal. Calcd. for C1SH1602: C , 81.79; H, 6.10. Found: refluxed for 1 hr. Homoveratrylamine hydrochloride (1.91 g.) C, 81.94; H , 5.99. 9-( p-Carbomethoxyethyl)-5,8,8a,9,lO,lOa-hexahydro-9,lO-o- was filtered, and the filtrate was washed twice with dilute HCl and dried (hIgS04). The benzene was distilled, and the amide benzenoanthracene-5,8-dione (11, R = CHZCHZCOOCH~).-A was crystalliLed from methanol; yield 4.3 g. (go%,). solution of 26 g. of pure quinone and 26 g. of 9-(@-carbomethPreparation of Amines by Reduction with Lithium Aluminum oxyethy1)anthracene in 350 ml. of ligroin (b.p. 80-100") was reHydride.-The amines 3, 12, 14, 26, 30, 36, 38, 40, 42, 44, 49, fluxed for 45 min. The solution was cooled, and the product (39 and 54 were prepared by reduction of the corresponding isocya9.) was filtered and recrystallized from a mixture of benzene and nates, amides, nitriles, oximes, carbamates, etc. (see charts) ligroin; yield 30 g., m.p. 186-189'. using an equal weight of LiAlHa in either tetrahydrofuran or Anal. Calcd. for C24H2004: C, 77.45; H, 5.41. Found: benzene-ether mixtures. The following will illustrate the genC, 77.67; H , 5.49. eral procedure. Preparation of Triptycenes by the Friedman and Logullo 9-( 7-Methylaminopropy1)triptycene Hydrochloride (38).-To Procedure.9-The derivatives listed in Table I %-ere made by a solution of 2.0 g. of LiAlH4in 35 ml. of dry tetrahydrofuran was either of the methods given below for 32 and 7. No attempt added dropwise with stirring during 30 min. a solution of 2.0 g. was made to study conditions to maximize tbe yields. of the amide 37 in 50 ml. of tetrahydrofuran. Stirring was 9-( 6-Carbomethoxyethy1)triptycene (32).-A solution of continued at room temperature for 1 hr., after which time the 157.5 g. of 9-(p-carbomethoxyethyl)anthracene and 138 ml. of mixture was refluxed for 45 min. The solution was cooled and amyl nitrite in 1500 ml. of methylene chloride was added dropwise during 4 hr. to a stirred and refluxing solution of 118.5 g. of anthranilic acid in 600 ml. of acetone. Refluxing was continued (20) When excess thionyl chloride at reflux temperature u-as used in for 15 rnin., after which time the mixture was cooled and washed this preparation, the acid chloride lost HC1 and cyclized to form t h e atwice with dilute HC1 and twice with saturated aqueous S a H C 0 3 . tetrelone derivative i, m.p. 301-305O, after crystallization from Methyl The solution was dried, and the solvent was distilled in uacuo. The product was crystallibed from methanol; yield 108 g. Triptycene-9-carboxaldehyde Ethylene Acetal (7).-To a stirred and refluxing solution of 122.5 g. of anthracene-g-carboxaldehyde ethylene acetal in 1225 nil. of dioxane was added simulethylanthracene was made from 9-P-hydroxyethvlanthracenele using the following procedure described for l-p-hydroxyethylnaphthalene.'? 9-~-Chloroethylanthracene.-Thionyl chloride (2.3 ml.) was added slowly to a mixture of 6.6 g. of 9-&hydroxyethylanthracene, 3.0 ml. of dimethylaniline, and 25 ml. of benzene. The solution was warmed for 30 min. on a steam bath, after which it was diluted with 3 vol. of ether. The mixture was washed first with water, twice with dilute HC1, and once with aqueous NaHCO3. The ether solution was dried and concentrated, and the crude product was crystallized from ether-petroleum ether; yield 4.14 g. (57$'), m.p. 57-90'. Recrystallization raised the melting point to 90-91.5'. Anal. Calcd. for ClsH&l: C, 79.82, H, 5.44; C1, 14.73. Found: C, 79.39; H, 5.69; C1, 14.82. 9-Hydroxymethy1anthracene.-To a solution of 10.3 g. of 9anthraldehyde in 100 ml. of warm ethanol was added 3.8 g. of NaBH4 in small portions with stirring. The mixture was allowed to cool to room temperature. Water was added, and the product was filtered, washed with water and ethanol, and dried; yield 10.0 g. (96%), m.p. 158-161'. S-Chloromethylanthracene.-Dry HC1 was passed into a warm solution of 4.0 g. of 9-hydroxymethylanthracene in 80 ml. of ethanol keepisg the temperature a t 30-40". The mixture was cooled in ice, and the product was filtered, washed with cold ethanol, and dried; yield 3.01 g., m.p. 132-133".'8 9-( p-Carbomethoxyethy1)anthracene.-A solution of 133 g. of 9-(p-carboxyethyl)anthracene19 in 4.5 1. of methanol was saturated with dry HCl below 25'. The solution was kept a t 25' overnight and then concentrated t o dryness in uacuo. The crude ester was crystallized from methanol; yield 132 g., m.p.
(16) B. hl. hlikhailor, I z c . A k a d . S a u k S S S I ? . , Old. Rliim. Srruk, 420 (1948); C h e n . Abslr., 43, 208; (1949). (17) J. IV. Cook and C. L. H e n e t t . J . Chem. Soc., 1098 (1933). (18) IV. T. Hunter, J. S. Buck, F. TI-. Gubitz, and C. H. Bolen, J . Org.
Chem., 21, 1512 (1956). (IS) G.H. Daub and IT. C . Doyle, J . Am. Chem. Soc., 72, 4449 (1952).
Cellosolve-methanol. Anhydrous H F also effected the same cyclodehydration of t h e acid. Anal. Calcd. for C28HleO: C , 89.58; H, 5.23. Found: C , 89.33; H , 5.45.
May 1965
FLUORENES. XIX. POTEXTIAL AKTITCIIOR COMPOUNDS
347
53 using excess dry KHBin ether solution, and the amide was reduced with LiAlH4 by the general procedure above to yield the amine hydrochloride 54. 13-(9-Triptycyl)-6-ketotridecanoicAcid (55).-The acid chloride of 8-(9-triptycyl)oct,anoicacid (52) was used to acylate the niorpholine enamine of cyclopentanone by the procedure used above. The crude p-diketone on alkaline hydrolysis afforded the ket'o acid 55. 13-(9-Triptycyl)tridecanoieAcid Amide (56).-\Volff-Kischner reduction of the ket,o acid 55 by the procedure used for 52 gave the t,ridecanoic acid, which vias converted to the amide 56 in the usual nay. Reduction of t,he amide afforded the amine hydrochloride 57. 12-(9-Triptycyl)dodecylamine Hydrochloride (58).-Hofmann degradation of the amide 56 was carried out using the procedure employed with 35. The crude carbaniate so formed was hydrolyzed by the method used for conversion 27 + 29 above.
a t 35-38" was continued for 30 min. The reaction mixt'ure was kept overnight a t room temperature, after which 25 ml. of 6 S HC1 was added. The mixt,ure was stirred a t 35-42" for 30 min. The chloroform layer was separated and washed with wat'er, and the solvent was distilled i n z~acuo. The residue %-ascrystallized from ether-petroleum ether; yield 8.5 g., m.p. 193-203". A sample vias recrystallized from ethylene dichloride-etherpetroleum ether. 5-(p-9-Triptycylpropionyl)valeric Acid (51).--4 solution of the diketone 50 (i.85g.) and 0.95 g. of NaOH i n 100 nil. of ethanol was refluxed for 4 hr. Concentrated HC1 (2.5 ml.) was added, and most of the ethanol wds distilled in w c u o . The product was filtered and washed with water; yield 7.5 g., m.p. 193-197'. il sample was recryst,allized from toluene for analysis. 8-(9-Triptycyl)octanoic Acid 152).-A mixt,urc of 7.3 g. of the keto acid 51, 1.05 g. of KOH, i . 5 ml. of 85r; hydrazine hydrate, and 20 ml. of diethylene glycol was stirred and refluxed for 6 hr. Diet,hylene glycol (20 v.1.) and 5 . 5 g. of KOH were added, and the niixture was heated for 17 hr. in an open flask in an nil bath kept a t 195". Thc reaction mixture was poured into several volumes of water. Then 12 S HC1 (20 nil.) was added. and the mixture was heated, then cooled, and the product was filtered and washed well with water; yield 6.7 g., m.p. 160-168". It vias recrystallized from met'hanol-ether. The acid chloride was prepared using oxalyl chloride according to the proredure given above for the acid chloride 34. This was converted to the amide
Acknowledgments.-The authors thank 11r. W. L. Brown and associates for the microanalyses, and Dr. H. Boaz and co-workers for physical data. The mouse behavior studies were carried out by N r . R. W. Kattau, and the antiinflammatory assays by Dr. R. Kraay and his associates. __
Derivatives of Fluorene. XIX.'' 9-o-Chlorocinnamylidenefluorene and Related Compounds T. LLOYDFLETCHER, 1\IOSES J. SAMKUSG, JOHX R. DICE,A S D SASDRAI
