September 1967
ASALGESIC~ - ( ~ - L > ~ ~ ~ E T H Y L A M I N O P R ~ P Y L ) - ~ L - M E T H T L - ~ - P H E ~ ~ ~ L - ~ - I ~ ~ ~ ~ ~ ~ L S
l-(3-Dimethylaminopropyl)-2-methyl-2-phenyl-l-indar~oland Related Compounds. A New Class of Analgesic Agents' CHESTERF. TURKAKD JOHSKRAPCHO ?'he S p u ~ b bInstitute jor Medical Research, S e w Brunswack, .Yew Jersey
08903
Receaved d p r z l l Y , 1967 T h e syntheses CJf the two racemates of the title cvJmpouiid aiid 17 analogs and derivatives are reported. 811 of these compouiids were tested orally for analgesic activity i n mice iisiiig a tail-flick procedure. Three of these products were more active than codeiiie sillfate.
2-;\lethyl-%-phenyl-l-indanone was subjected to a variet'y of chemical reactions and the products were submitted for pharmacological evaluation. The interaction of I with 3-dimethylaminopropylmagnesium chloride (11) in tetrahydrofuran gave a high yield of a mixture of the two racemates of the title compound. After complete separation by selective ctrystallization, the racemates were converted to hydrochloride salts (designat'ed as a arid p forms) arid tested orally for analgesic activity in mice using a tail-flick p r ~ c e d u r e . ~ The a form (1) was found to be more active than the p form (2) or codeine sulfate by this method. The infrared spectra (in CDCI,) of these isomers showed a distinct difference in the absorption frequency of the hydroxy group: the Q form at 3590 cm-' arid t'he form a t 3556 (mi-'. The absorption frequency of the p form indicates that the hydroxyl is bonded t o the T electroris of the phenyl group,j thus requiring these groups to have a cis configuration, whereas the normal rionbonded hydroxyl and phenyl groups of the CY form are in a trans position. These st>ructural assignments were in agreement with the subsequent nmr studies, the details of which will be the subject of a separate paper.6 In order to determine a structure-activity correlation in this class of compounds, '>,3-dimet,hyl-'>-phenyll-indanone3 arid 2-methyl-2-phenyl-l-tetralone' were treated with 11. I was also treated with the Grigriard reagents derived from 4-chloro-X-methylpiperidirie and 3-(methylphenethylaniino)propyl chloride (obtained from the reaction of allyl alcohol with methylphenethylamine, followed by treatment of the resulting propanol with SOC12). The analog of 1 coritainirig a t,wo-carbon side chain (10) was obtained by the treat'merit of I with a-bromo-S,S-dimethylacetamidein the presence of zinc dust, followed by the Li,UH1 reduction of the amido intermediate. The products of these reactions are listed in Table I. I n addition to these carbinols, the relat,ed tricyclic compound, 9-(3dimethylaminopropyl)fluoren-9-o1,*was prepared for (1) Presented in part before the Diyision of Aledicinal Chemistry, l 5 l s t National Meeting of t h e .lmerican Chemical Society, Pittsburgh, P a . , M a r c h 1966. (2) N. Campbell a n d E. Cipanek, .J. C h e m . Soc., 3835 (19%). ( 3 ) The a u t h o r s are indebted to Dr. 11. I3rrison of tile Oiin Research Laboratories for a s u ~ i p l yof this material. .\ description of a new one-step synthesis of this indanone is disrlosed b y Olin blatliieson Chemical Corp., I3elgian Patent 67ti.372 (.lug 11, 1966). ( % ) R. Rubin, J . Kraprho, and J. P. High, L i f e S c i . , 6 , 845 (1968). (.5) P. von R. S r h l ~ y e r ,C'. IYintner. D. H. Trifan, a n d K. Karnkai, Tefrah w / m n Letters. No.1 4 , l ( 1 9 5 9 ) . 16) A . I. Colien a n d 13. T. Keeler, submitted for priblication. ( 7 ) H. Christol, C. Martin, and 11. AIousseron, Bull. SOC.Chim. F r a n c e , 1696 11960). (8) G. E. I3onvicino. FI. G. .'irii,, K. hI. Pearson, a n d R . A. Hardy, J . Uru. Chem., 26, 2383 (1901).
coniparisori with 1 . Treatment of the free base of 1 with propionyl chloride in CHC13 (an attempt t o obtain an ester of 1) yielded the dehydration product (12). The latter indanylidene was then hydrogenated to the corresponding indanyl analog (13). I n a similar manner, the piperidine indariol (6) was converted to 14 and 15. Treatment of 1 with a mixture of HC1 and acetic acid resulted in the conversion to the carbonium ion arid subsequent migration of the phenyl group to the 1 position to give l-phenyl-S,S,2-trimethyl-l-indenepropylamine (16). The same migration of the phenyl group took place when the piperidine (6) and naphthalene (9) analogs were made to react to give 18 and 19. Hydrogenation of 16 gave the corresponding iiidariprop\.l:tniiiie (17). All of the compounds of Table I were tested for analgesic artivity by the oral route in mice using a tailflick procedure;4 three of these (1, 3, and 8) were more active than codeine sulfate in this test procedure. 111 a direct comparison, 1 was found to be slightly more active than codeine sulfate in mice when administered by the intraperitoneal route. I n each case where two racemates were separated from the reaction, the Q form (hydroxyl and phenyl in a trans configuration) was more potent than the p form. Seither of the isomers of the piperidine compound (6 arid 7), or the dehgdration product (14) showed significant analgesic activity. The latter material exhibited weak aritihistamiiiic and antiserotonin properties. -411 of the other abovementioned modifications of 1 showed a lower order of analgesic ac tivi ty . Experimental Section Melting points are con,ected. Infrared spectra were recorded on a Perkin-Elmer M o d e l 21 spectrometer aiid t h r nmr data (CDCla) were obtaitied with a Varian Associates Model -460, with hIe4Si as ai1 iiiteriial reference standard.
I-(3-Dimethylaminopropy1)-2-methyl-2-phenyl-l-indanol Hydrochlorides (1, 2).-A suspension of 48.0 g ( 2 . 0 g-atoms) of 1 I g powder in 180 ml of dr!: tetrahydi,ofur,ati ( T H F ) was treated with about 150 ml of a rolutiori of 240 g (2.0 moles) of 3-dimethylaminopropyl chloride i i i $20 ml of THF. A few crystals of iodiiie were added and the mixture M-RS geiitly heated to about 66". The reactioii hecanie eroi herniic atrd was coiitrolled hy brief caoolirig i t i a11 ice h t h . The mixtiire w a s theii allowed to i,efliis cluriiig the additioti of thr rernaiiider of the 3-tlimethylami110ptupyl chloi,ide solutioii aild coi~tiiiiietlfoi, ail atlditioiial 30 m i i i . The exteriial heatiiig wa.: discoiltiiiiied tliuiiig the :idditioil ( 2 0 inill) of a soliitioii of 1.50 g (0.6smole) of 'L-nieth!.l-2-pheti!~l-1it1~1aiii)iie~ i t i 160 nil of TITF, m i d the i,esiiltiiig mistlire was refliised for 6 hr, cooled, and the11 added to a (>oldsoliiti~iiof (300 g of SH,CI it1 4.5 1. of water. The mistiire was extracted several times with ether, the orgaiiic phase< were coml~iiiedaiid dried (AIgSOa),aiid the solveiits were removed uiider reduced prewire
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The latter alliiie residtle, mp 93-120'. i o give 202 g of ci material was digested with 1.11. of hut hexane leaving 24.5 g of illsoliihle prodiict, nip 125-129'. T h e solid which separated from the cooled hexane sollition weighed 137 g, mp 95-120". T h e latter material was piilverized and tritiirated with 600 ml of ether for 10 min, the insolitble prodiict (42 g, mp 128-131') was a t w e d , arid the filtrate (combined with t'he above hexaiie mother liqiior) was evaporated to give 115 g of solid, mp 92-96'. This material was crystallized from 420 ml of hexane t o give 91 g of the free base of 1, mp 98-100". -4naZ. Calcd for C21R2iNO: C, 81.51; H, 8.80; 1;, 4.53. Forind: C, 81.43; IT, 8.97; N, 4.50. A solution of 91.0 g of base in 1.2 1. of ether was treated with ail equivalent quantity of ethereal HCl to give 96.5 g of colorless solid, mp 163-165'. This material was dissolved in 600 ml of ethanol at room temperature and diluted with 6 1. of et'her to give 78.0 g of crystalhie prodiict. T h e above higher melting fractious (24.5 and 42.0 g) were combined and crystallized from 320 ml of acetonitrile to give 51.0 g of the free base of 2, mp 134-136". Anal. Calcd for C21H27NO: C, 81.51; 11, 8.80; N, 4.53. Foiind: C, 81.32; H, 8.64; S , 4.31. A solution of this base in 250 ml of CHCL was treated with an equivalent quantity of alcoholic HC1 and diluted to 2 1. with ether to give 55.0 g of material, mp 170-172". A mixture of 1 and 2 (recrystallized products) melted a t 162165'. One significant difference in the infrared spectra (Nujol mull) of these isomers was apparent; 1 showed a characteristic band a t 753 em-' and 2 at 766 em-'. I n the form of the free bases, t,hese hands were shown a t 763 and 772 cm-l, respectively. 1-(2-Dimethylaminoethyl)-2-methyl-2-phenyl-l-indanol Hydrochloride (lo).-A solution of 10.0 g (0.045 mole) of 2-methyl2-phenyl-1-indanone and 9.0 g (0.054 mole) of a-bromo-N,Ndimethylacetamides in 30 ml of benzene was added portionwise to a stirred and refluxing suspension of 3.6 g (0.055 g-atom) of zinc dust in 10 ml of benzene (containing a trace of I?). This mixture was refluxed for 3 hr, cooled to 5 O , and treated portionwise with 25 ml of 10% H2S04. T h e layers were separated, and the organic phase was washed (NaHC03, H?O). After drying (IIgSOd), the solvent was evaporated a t reduced pressure to give 11.4 g of a semicrystalline mixture of the hydroxy amide and starting ketone. The above material was dissolved in 150 ml of ether and added to a stirred suspension of 5.0 g (0.13 mole) of LiAlHd in 300 ml of ether, and the mixture was refluxed for 6 hr. T h e product (10.5 g of syrupy material) was isolated in t'he usual manner, dissolved in 400 ml of ether, and treat'ed with an eqiiivalent quantity of a solutian of maleic acid in ether to give an oily maleic acid salt. The latter was dissolved in 25 ml of butatione and diluted with ether to give 5.0 g of solid, mp 127-130". An aqiieoiis solution of this salt' was treated with excess K&03, the liberated base was extracted with ether and dried (MgSO1), aiid the solvent was evaporated t,o give 3.2 g of base, mp 100103'. After crystallization from 15 ml of hexane, the material weighed 2.3 g, mp 106-108". dnal. Calcd for CS1H2jiYO: C, 81.31; H, 8.53; N, 4.74. Found: C, 81.34; H, 8.71; N, 4.60. The above base gave 2.4 g of the HCI salt. N,N-Dimethyl-3-( 2-methyl-2-phenyl-1-indanylidene)propylamine Hydrochloride (12).--A solution of 10.0 g (0.029 mole) of 1 in 200 ml of CHCI, was cooled in an ice bath and t'reated with (9) \\-. E. \\ ea! er aiid
I\-.AI. I\ I i a l e ~ J. , A m . Chem. Soc., 69, 615 (1947).
a solution of 3.2 g (0.035 mole) of propioliyl chloride i n 75 1111 of CHCl3, aiid the resulting solution was allowed t o staiid at room temperature for 12 hr. The solvent was removed under reduced pressure and the residue was triturated with 200 ml of ether to give 9.5 g of solid, mp 80-83". Nmr on the piirified material showed a siiiglet at T 8.32 (CH,) and a multiplet ceiitered a t 4.17 (olefinic pwtoii of =CHCH,). N,N-Dimethyl-3-(2-methyl-2-phenyl-1-indanyl)propylamine Hydrochloride (13).-A mixture of 3.6 g (0.11 mole) of 12, 3.0 g of 5y0Pd-C and 100 ml of ethanol was placed on a Parr apparatus under 3 atm of hydrogen at room temperature. T h e theoretical quantity of hydrogen was consumed in 15 min. The mixture was filtered, the filtrate was concentrated under reduced pressure! and the residue was triturated with 100 ml of ether to give 3.1 g of colorless product, mp 224-226'. l-Phenyl-N,N,2-trimethyl-l -indenepropylamine Hydrochloride (16).-A mixture of 10.0 g (0.029 mole) of 1, 160 ml of CH,COOH, and 60 ml of concentrated HCI was heated and the resulting solution was refluxed for 3 hr. T h e solution was concentrated under reduced pressure and the residue was tritiirated with a mixtiire of acetoiie and ether t o give 5.5 g of prodiict, mp 138-140'. Nnir on the purified material showed a doublet centered at T 8.24 ((3113 protons of CH,C=CH) and a qtiartet' ceiitered at 3.45 (olefinic proton of CH,C=CH). This material was hydrogenated (4-hr pet,iod) to give 17 iii the maimer described for 13. 3-(N-Methylphenethylamino)-l-propanol.-.4 stirred mixture of 82 ml (1.2 moles) of allyl alcohol and 16.0 g (0.40 mole) of powdered XaOH was warmed to 65', treated with 54.0 g (0.40 mole) of N-methylphenethylaniine, aiid then refluxed for 7 hr. Water (200 ml) was added, aiid the mixture was distilled until 100 ml of distillate was collected. The cooled residue was extracted with 200 ml of CHCI, (three times), the extracts were combined and dried (MgSO,), and the solvent lyas evaporated. Fractionation of the residiie gave 19.0 g of the starting amine and 30.0 g (60%, based on recovered starting material) of the product, bp 132-136" (2 mm). Anal. Calcd for C12H1JO: ?$, 7.25. Fornid: S , 7.37. N-(3-Chloropropyl)-N-methylphenethylamine.-A solution of 41.0 g (0.21 mole) of the above material in 110 ml of CHCI, was treated with 33 ml of SOCI? and refluxed for 2 hr. About 50 ml of liquid was distilled, arid the residue was cooled and diluted with 200 ml of ether t o give 50.0 g of the hydrochloride, mp 125-128". The analytical sample was crystallized from acetonitrile, mp 131-133'. Anal. Calcd for Cr211IuC1,S: C1, 28.2,5; S , 5.49. Found: C1, 28.57; X, 5.64. The hydrochloride wab susDended in 7.5 ml of rold water and treated 471th a cold sollitton oi 32.0 g of KzCO? i n 30 ml of water, and the liberated base was extracted with ether. T h e ethereal solution was dried (JIgSOA), the solvent w a i evaporated, and the residiie was fractionated to give 33.0 g ( 7 4 5 ) of prodlict, bp 98-100" (0.3 mm) Anal. Calcd fox CIIH&l?;. S, 6.62. Found: N, 6.81.
Acknowledgments.-We are indebted t o Dr. J. Bernstein for his interest and encouragement during this investigation, to Dr. J. Burke and his associates for the pharmacological data, to l l i s s B. T. Keeler for the infrared data, to Dr. A. I. Cohen for interpretation of the nmr spectra, and to A h . J. Alicino arid his associates for the analyses reported herein.
