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    Aminobenzylcyclanols PDF

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    Arch. Pharm. (Weinheim) 327, 525-528 (1994) Aminocyclanols, I: Synthesis and Analgetic Activities of Some Aminobenzylcyclanols Derived from Menthone Aminocyclanole, 1. Mitt.: Synthese und analgetische Wirkung einiger vom Menthon abgeleiteter Aminobenzylcyclanole Ozdemir Ozarslan®, Mevitit Ertan®, Tugmag Sayrag”, Hulya, Akgiin®, Riimeysa Demirdamar®, Billent Guimiisel” 4) Hacettepe University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, 06100 Ankara, Turkey ») Middle East Technical University, Chemistry Dept, 06530 Ankara, Turkey ©) Hacettepe University, Faculty of Pharmacy, Dept. of Pharmacology, 06100 Ankara, Turkey Several cyclobexanamines such as Tilidin'), Tramadol* ®, and Ciramadol*” have been used as opiate analgesic drugs*6™6.7, Here, we describe synthesis and analgesic activity of some aminocyclanols from (-)-menthone (IR,4S- 1-methyl-4-isopropyl-cyclohexan-3-one). ‘Two synthetic routes are described for the preparation of amino-benzylcyclanols and related derivatives’): One is the reaction of at-benzylidenecyclanones with various ami- nes to obtain aminobenzyleyclanones which upon reduction yield amino-benzyleyclanols®"®). In the other approach, benzisoxazols are first formed from benzylnitrones and cycloalkene, then treatment of benzisoxazoles with an allyl- halide produces the corresponding benzoxazoline halide and hydrogenolysis of these halides give the desired com- pounds)”, In this work, (-)-menthone (1) was reacted with benzalde- hyde in the presence of base in dry ether to yield an E/Z- isomere mixture of 2-benzylidenecyclohexanone 2, 3. Only the £ isomer reacted at room temp. with some cyclic sec. amines to yield compounds 4a-d. Compounds 4a-d were then reduced with LiAIH, to give the corresponding amino- alcohols 5a-d (Scheme 1). Results and Discussion 2-Benzylidenmenthone 2, 3 could not be synthesized with the procedures in lit. reported because of low yield (Table 1). We improved the yield to 46-56% using NaH in dry diethyl ether instead of aquos NaOH, sodium ethoxide or piperidine in an organic solvent®"), oH ()Ciramadol rac Tilidin The E/Z ratio in 1R,4S-2-benzylidene-1-methyl-4-isopro- pyl-cyclohexan-3-one was determined by GC analysis: E = 68% and Z = 31 %, Baltzly and other groups*"®) showed that trans benzylidene-cyclohexanones give Michael type addition with sec. amines. In our study only the E isomer 3 gave an addition product with cyclic amines. All attempts were unsuccessful with the Z isomer 2. The Claisen-Schmidt product of rac-camphor was also synthesized with the £/Z ratio 6/94 but this mixture did not undergo any addition reaction with all sec. amines consid- ered. ‘The C-2 and C-11 centers of compounds 4 may cause the formation of four isomers during the addition of sec. amines. However, we obtained only one diastereomer. This result indicates the high stereoselectivity at these two cen- ters. The stereochemistry of these compounds will be pub- lished separately. 2-(a-Aminobenzyl)-(-)-menthones 4 were reduced with LiAIH, to obtain the corresponding aminoalcohols Sa-d 16), These compounds show reduced analgesic activity only (Table 2) as compared with the ketones 4a-d. Preliminary pharmacological screening Methods Animals: Local bred male albino mice weighing 20 + 2 g were housed in groups of six with free access to food and water. Hot plate test:'*!9), Animals were placed on the hot plate and the latency to the first hind paw licking was pct (CHale / WON LOH How NCH “ COL Hs rac-Tramadot Cyr . ° (©Menthone Natt Dryether 4 a Axo @2 —O) Ropar +) un ‘OH Sa-sd Scheme 1 H ‘oO ®3 2 a)piperidi b)pyrrolidine ‘)N-methylpiperazine @)morpholine Table t: ‘Table 2: Response to latency in the constant temp. hotplate test. Compound Base Solvent Reae. Time Yield % Latency (6) othe First hind paw licking (-Menthone NaOH (10%) Water Ghreflux 5 Pruss Tes compound ee NaOH (50%) Water 6hreflux 10 - - NaOH 6) Ghrollux 16 a 248i 213 214043.1 NaOH() —Dryether—Ghyreflux 12 4b 231s" 419 24.00+2.3 Na=Ei(139%) Abs. EO 6hyreflux M4 4e 1533415 2320420 Nall Dryether 6 hyreflux 45 4a 21.83°+2.0 2.10419 L-Camphor NaOH (50%) Water Ghvreftux 16 5a 1146417 194028 Natt Dryether — 6hvreftux 56 3b 833414 2498418 — - Se 1050420 24804211 recorded. The test was terminated if no hind paw lick 54 983 E14 18.2029 occurred in 30 seconds (Table 2). The data were analysed "smadol 16.13 +4203) 21014 by Anova, morphine 18.6642.4 0) control 8.00419 Table 2 shows the preliminary results: 4a-d enhanced the _ latency to the first hind paw licking. The values obtained (= 6 per group) were significantly higher than those of tramadol and mor- phine. ‘Compounds de, Sa-d were not as active as the other com- pounds, but again they enhanced morphine analgesia. Naloxone did not induce withdrawal syndromes in mice that received the compounds 4a-d, however, with com- pounds 4e, 5a-d withdrawal symptoms were observed. 1) LS mgike ip injection 2) To 10 mg/kg morphine received mice the test compounds were admini- stored. *) No withdrawal syndromes after injetion of naloxone following 5 days of test compound administration, 3) 25 mg/kg ip injection of wamadol-HCL 4) 5 mgkkg ip injection of morphine-HC1. Experimental Part Melting points: Reichert hot stage melting point apparatus, uncorrected, lemental analyses: Hewlett Packard 185 CHN analyser.- IR-spectra: Uni- ‘cam 9706 IR-spectrometer.- ‘H-NMR spectra: Bruker FT 80 MHz, CDCI, ‘TMS as internal standard, Chemical shift in 8 (ppm) - ELMS: VG TR 10- 2.GC-mass spectrometer.- Metck silcagel 60 HF 254 was used for analy cal and prep. tle Column chromatography: kieselge! 100 (70-230 mesh), ‘mobil phase a) diethyl etherfhexane 1:15, b) diethyl etherfbexane 1:5. 1R4S-2-Benzylidene-1-methyl-4-isopropyleyelohexan-3-one (2,3) (mixture of diastereomers) 30 g of (-methone (1) and 5 g (excess) NaH were sted for 30 min at 25°C in dey ether. 20 g (0.19 moles, 20 mil) of redistilled benzaldehyde Were introduced dropwise during 2h. A solid mass was decomposed with 50 ml N HCl. The supematant layer was extracted with ether and washed With sad. NalICOs, Euher was evaporated at 15 torr, the erade material ~vas purified by ce (column chromatography) with mobile phase (@): 14.4 8, 32%, Mp. 3 (E) = 48-51°C, 2 (2) = 46-89°C, RE: E = 0.77, Z = 0.70 (enobil phase a) CijPfg0 (242.3) Caled. C 84.3 H 9.0 Found C 84.2 H 9.16. IR (CHCL}: 1675 em! (C=O of E), 1695 em! (C=O of Z). 1590 em? (C=C of E), 1600 em" (G=C of 2) "H-NMR (CDCI: 0.96 (6H: m: (CH, 12 GH; ds J 7.1 He, 1-CH), 18 4H; my 56-CH), 2.16 OH: sn; LH 81), 344 (1B my 419), 702 IHG 5; UH 2), 7.43 (UME 5, HLL (©), 73 (SH: m, CeHig~ C-NMR (CDCI) 205 (C=O) (E), 203 (C=O) ©), 143 and 1409 (C-11"s of (E) and (2), 1262-129.2 (arom. C), 60 and 59.1 (C-2's of (E) and (2), 57.8 and 55.6 (C-1°s of (E) and (2), 535 (C- 4), 31.7 (C5, C6), 27.6 (C10), 19.5 (C8, C9) MS (70 eV): miz (ebimens.%e) = 242 (M*; 60), 200 (50), 171 (80), 129 (100), 91 (75), 77 (15), Same for both isomers. 1RAS-2-(crAminobenzy)-I-methyl-4-isopropyl-eyelohexan-3-ones (4) 2 g (8.2 mmoles) of 3 or mixture of 2 and 3 were dissolved in an excess ‘of amine and allowed to stand at room temp. for one or two days. After the reaction mixture had solidified, the solid material was suspended by cold dry ether and filtered to give white crystals. The filtrate was extracted three times with N HCI, The acid phases were combined and basified with NaOH, The oily precipitate was extracted with diethyl ether and dried over ‘MgSO,. Removal of ether gave a white crystalline product which was combined with the previously recovered crystals. Recrysallisation from cther:hexane (1:2). IRAS-2-(C8N-Piperidinobenzyl)-I-methyl--isopropyl-eycloheran-3-one 4a) 16g, 95% related 19 3. Mp, 141-143°C.- RE: aminobenzyl-menthones are rather unstable on silica and alumina based tle. CysHyyNO (327.3) Caled, € 80.7 Hf 10.15 N 4.3 Found C 80.4 1988 N 4.0~ IR (HCL) 1680 em! (C=0)~ "H-NMR (CDCI): 0.8 (OH: ms (CH) and -CH), 1.47 (6H, m; pip. (CHa). 1.9 (6H, m; menthone (CH:)), 2.28 (4H: mi; pip. (CHa), 2.7 OH mi 4-H), 34 (IH dds 2H, Jo) = 174 Ha, Jay = 4.8 Ha), 38 (IH d; LL-H, Jyya = 11.74 Hz), 7.2 (SH: m; arom. H).- C- NMR (CDC): 211 (C=O), 137 (C22), 127-1283 (arom. ©), 64.7 (C19, 58.1 (CA), $5.5 C1), 50.1 (C-1), 38 (pip. C-2, C-5), 32.7 (C-5 and C6), 26 (pip. C-3, C-5, C-8).~ MS (10 eV): mle (FeL.intens.%6) = 327 (M (0465), 242 (60), 200 (40), 174 (90), 171 (60), 129 (100), 91 (95). IRAS-2-(CN-Pyrrolidinobenzyl)-1-methyl-4-isopropyl-eyclohexan-3-one (ab) 1.5 g, 92% related to 3. M.p. 144-147°C.- CyyH,NO (313.5) Caled. C 80.5 119.96 N 4.5 Found C 80.4 H 10.11 N49.- IR (CHCl): 1685 em? (C=0).- 'H-NMR (CDCI): 0.75 (9H: my; (CH)p and 1-CHy), 1.54 (4H; m; yr. (CHa}), 1.96 (4H; m; (CH,),), 2.33 (41; m; pyre. (CH,)2), 2.76 (1H sm: 4-H), 3-4 (Hs dds 2-H, Jnay = 11.74 Ha, Jn =4.8 He), 1 (1H ds 1 H, Jyyq = 1.74 Ha), 7.2 (SH; m; arom. H)- MS (70 eV): m/z (el.intens.%) = 313 (M"; 0.50). 242 (25), 200 (13), 171 (15), 160 (100), 129 (30), 91 (400), 70 18), IRAS-2-(CeN.N'-Methylpiperazinobeneyl)-1-methyl-4-isopropyl cyelohexan-3-one (4e) 1.6 g, 87%, related t0 3. M.p. 144-147°C.- Cry4NjO (342.5) Caled. C 77.1 H 10.0 N 82 Found C 77.1 H 100 N 8.1. IR (CHCL): 1670 em! (C=0)~ 'H-NMR (CDCI): 0.8 (9H; m; (CH3)2 and 1-CH,), 1.96 (4H; m; (CH,);), 2418 (GH; s; N-CH,), 2.36 (8H; my; piperaz.(CH),), 2.8 (1H m; 4 FD, 3.36 (IH; dd 2-H, J, = 11.74 Hz, J, = 4.8 Hz), 2.89 (1H; d 1-H, Jy.2= 11.74 Hz), 72 (SH: m; arom. H).~ MS (70 eV): m/z (e.intens.%) = 342 (MP; 12), 242 (50), 200 (25), 189 (100), 171 (50), 129 (60), 91 (75), 70 (52), IRAS-2-(@cN-Morpholinobenzyl)--methyl4-isopropyl-eyclohexan-3-one (4a) 1.6 g, 90%, related 10 3. M.p. 148-150°C.- CHyyNO, (329.5) Caled. C 76.55 H 9.48 N 4,3 Found C 16.5 H 9.66 N 4.8,- IR (CHCL): 1680 em" (C=0).- "H-NMR (CDCI): 0.48 (9H; my; (CH), and 1-CH,), 1.94 (4H; m; (CH,),), 2.29 (AH; t; morph, N-{CH,)2), 2.79 (1H; mm; 4-H), 3.39 (TH; dd, 2H; Jy, = 11-74 Hz, Jy = 4.8 Hz), 3.6 (4H & morph. O-(CH3)n), 387 (UH; d 1-H, Jy = 11.74 Ha), 7.24 (SH; mm; arom. H)- MS (70 eV): sz (el.ntens.*%) = 342 (MP; 12), 242 (50), 200 (25), 189 (100), 171 (50), 129 (60), 94 (95), 70 (32). IRAS-2-(0N-Aminobenzyl)-1-methyl-4-isopropyl-

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