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Letters in Drug Design & Discovery, 2009, 6, 78-81
Solution-Phase Parallel Synthesis of N-Arylisoquinuclidines Ronald F. Borne1, Mark S. Levi*,2, M.O. Faruk Khan3 and Norman H. Wilson4 1
Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, School of Pharmacy, University of Mississippi, University, MS 38677, USA 2
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 3
College of Pharmacy, Southwestern Oklahoma State University. Weatherford, OK 73096, USA
4
School of Biomedical Sciences, University of Edinburgh, Edinburgh, Scotland, UK Received September 22, 2008: Revised October 22, 2008: Accepted October 28, 2008
Abstract: The naturally-occurring alkaloid ibogaine, found in the West African shrub Tabernanthe iboga, possesses the ability to diminish self-administration of substances of abuse, such as cocaine, heroin and alcohol. The presence of the isoquinuclidine ring system in the structure of ibogaine became the lead for the design of a 16-member library of N-aryl isoquinuclidines, where pyridine, pyrimidine and quinoline ring systems were attached directly to the bicyclic nitrogen. A solution-phase method for their synthesis is described.
Keywords: Addiction, Ibogaine, Isoquinuclidine, Parallel synthesis, Anti-addictive. In previous studies [1, 2], solution-phase synthesized, small-molecule libraries were developed containing structural analogs of ibogaine (1, NIH 10567, Endabuse™), a natural product isolated from the African shrub Tabernanthe iboga. Ibogaine has been widely studied as a treatment for substance abuse [3]. Reviews of the history, chemistry, mechanisms of action, pharmacokinetic properties, metabolism, neurochemical and anti-addictive properties of ibogaine have appeared [3-5]. Ibogaine possesses the ability to diminish self-administration of cocaine [6] as well as morphine [7] and alcohol [8]. These studies suggest that it may possess therapeutically useful anti-addiction and anti-craving properties, however its use has been restricted because of reports of neurotoxicity [9]. We have attempted to separate the beneficial anti-addictive properties from the neurotoxic effects by preparing various structural analogs of the parent alkaloid. N
H3CO N H
CH2CH3
1, Ibogaine
To date, few totally synthetic analogs of ibogaine have been synthesized and pharmacologically evaluated. Repke et al. [10] reported the synthesis and evaluation of indolotropane analogs of ibogaine. Among these indolotropanes, the most potent inhibitor of MK-801 binding was 15-fold less potent than ibogaine. Efange et al. [11] synthesized a group of phenyl-substituted analogs of 1,2,3,4,5,6-hexahydroazepino[4,5-b] indole, a major ibogaine fragment and five of those analogs showed 8-10-fold higher affinity for the *Address correspondence to this author at the Department of Pharmacology & Toxicology, Univ. of Arkansas for Medical Sciences, 4301 W. Markham, Slot 638, Little Rock, AR 72205, USA; Tel: +1 (501) 526-7823; Fax: +1 (501) 686-8970; E-mail:
[email protected] 1570-1808/09 $55.00+.00
dopamine transporter (DAT) than ibogaine and noribogaine, however all displayed poor affinity for the dopamine D1 and D2, μ and opioid receptors and the NMDA receptorcoupled cation channel. During our studies, the synthesis and preliminary pharmacological evaluation of several heteroaryl isoquinuclidines, specifically 7-heteroaryl-2-azabicyclo [2.2.2]oct-7-enes, was reported by Passarella et al. [12]. The absence of the azepine ring did not limit affinity for the DAT, serotonin (5-HT) transporter (SERT), kappa and NMDA receptor systems. Additionally, a series of 3,8diazabicyclo[4.2.0]octanes, which demonstrated agonist activity at the nicotinic acetylcholine receptor [13], was reported. It has been previously shown that quipazine (2) derivatives where a quinoline or naphthyl ring is attached to the piperidine or piperazine nitrogen are novel 5-HT1 and 5-HT2 agonists [14]. The series of N-substituted isoquinuclidines reported here was designed to eliminate the bond between the 6-position of the isoquinuclidine and the 2-position of the indole ring. Additionally, the 7-ethyl group was replaced with H to simplify stereochemical requirements as shown in Fig (1). The N-aryl substituents chosen were pyridines, pyrimidines or quinolines. Members of the library consisted of the intermediate 2-azabicyclo[2.2.2]oct-5-ene derivatives (3) in addition to reduced isoquinuclidines (4). Thus the compounds in the present study can be considered semirigid analogs of both ibogaine (1) and quipazine (2) where the isoquinuclidine ring system replaced the indole and piperazine rings of 1 and 2, respectively. FORMATION OF THE N-SUBSTITUTED ISOQUINUCLIDINES The requisite isoquinuclidines (5) and (6) were prepared as previously described [1]. © 2009 Bentham Science Publishers Ltd.
Solution-Phase Synthesis of N-Arylisoquinuclidines
Letters in Drug Design & Discovery, 2009, Vol. 6, No. 1 NH
N
H3CO
N
N
N H
CH2CH3 1 2
Ar
Ar N
N 4
3
Fig. (1). H
H N
N 6
5
Due to their instability (ability to absorb CO2 from air), the free amines were immediately alkylated. Various aryl halides 7{1-8} were utilized to synthesize the compounds of general structures 3 and 4. Reaction vessels were purged with argon, loaded with DMF, the diversity reagent (1.0 eq) and K2CO3 (1.0 eq). Lastly, amines 5 or 6, in benzene (1.2 eq) were added. The I N
reaction block was heated to 140ºC and mixing continued for 48 h. This method was useful for the arylation with the 2- or 4-substituted pyridines or quinolines 7{1-3, 6 and 7} to produce 3{1-3, 6 and 7} and 4{1-3, 6 and 7} in 30–60% yields. However, this method was not useful for the arylation with the less reactive 3-haloaryl derivatives 7{4, 5 and 8}. Two approaches were utilized to achieve arylation. Palladiumcatalyzed amination of the aryl halide with 5 or 6 in the presence of bicyclic triaminophosphine P[N(i-Bu)CH2 CH2]3N [14] and sodium t-butoxide afforded the corresponding arylamines in good yields (Scheme 1). Thus 1.0 eq of arylhalide and 1.2 eq of amines 5 or 6 were added to Ar-purged reaction vessels along with anhydrous toluene. The remaining reagents (1.5 eq of sodium tert-butoxide, 5.0 mol% Pd(OAc)2 and 10.0 mol% of the triaminophosphine) were measured in a N2 chamber, dissolved in anhydrous toluene, added to a sealed glass vial and transferred to the reaction vessel through a cannula. The reaction block was heated to 80oC and mixed for 24 h, then cooled to room temperature. The solvent was subsequently evaporated and the crude products purified with column chromatography. Alternatively, arylation of 5 with the 3-substituted heteroaryl halides 7{4, 5 and 8} yielded analogs 3{4, 5 and 8}. Subsequently, one-half of the products were hydrogenated overnight at 40 psi in ethanol over Pd/C using an Argonaut Endeavor® gas reactor to produce the reduced isoquinuclidines 4{4, 5 and 8}. This latter method had the advantage of avoiding the N
Br
N
1
Cl
Br 3
2
N
Br 4
CF3 N N
N
N
Cl
Br
CF3
N
Br
5
Br
6
8
7
Fig. (2). Diversity reagents 7{1-8}.
HN 5
ArX, K2CO3, DMF, 130oC, 48h
Ar N
or P[N(iBu)CH2CH2]3N, Pd(OAc)2, NaOtBu ArX, Toluene, 80oC, 12h
3
H2/Pd
HN
6
Scheme 1.
79
ArX, K2CO3, DMF, 130oC, 48h or P[N(iBu)CH2CH2]3N, Pd(OAc)2, NaOtBu ArX, Toluene, 80oC, 12h
Ar N
4
80 Letters in Drug Design & Discovery, 2009, Vol. 6, No. 1
inconvenience of moisture absorption during the transfer of the free amine 6, the palladium catalyst, the phosphorus ligand and t-butoxide from the glove box in which they were weighed to the reaction block. PURIFICATION Purification was achieved by silica gel (Grade 60A, Particle size: 63-230 μm (70-230 mesh)) column chromatography using hexane-ethyl acetate and employing Isco CombiFlash® Retreive™ automated flash chromatographic equipment. All structures were confirmed using 1H NMR analysis and mass spectrometry (MS) and C, H, N analyses of the final products. The compounds produced will be evaluated at the , μ and opiate, NMDA, -1, -2 and nicotinic receptors as well as the dopamine and serotonin transporters. These agents will hopefully provide insight into the mechanisms of action of ibogaine and quipazine. ACKNOWLEDGEMENT Financial support from the Centers for Disease Control and Prevention (1U01 CI000211-01) and the Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi is greatly appreciated. Analysis of Products of General Structure 3 3{1}: 1HNMR (CDCl3, ppm): 8.30 (1H, m, Ar), 7.40 (1H, m, Ar), 7.20 (1H, m, Ar), 6.20 (1H, m, Ar), 6.36-6.47 (2H, m, C-7 & C-8 double bond), 5.28 (1H, m, C-1), 3.20 (1H, m, C-3), 2.90 (1H, m, C-3), 2.78 (1H, m, C-4), 1.97 (1H, m, C-6), 1.60 (1H, m, C-6), 1.40 (2H, m, C-5). EIMS: 186.14 (M), 187.16 (M+1). 3{2}: 1HNMR (CDCl3, ppm): 8.25 (1H, m, Ar), 7.55 (1H, m, Ar), 6.26 (1H, m, Ar), 6.45 (2H, m, C-7 & C-8 double bond), 5.25 (1H, m, C-1), 3.20 (1H, m, C-3), 2.89 (1H, m, C-3), 2.84 (1H, m, C-4), 1.96 (1H, m, C-6), 1.40 – 2.00 (4H, m, C-5, C-6). EIMS: 313.0 (M + 1). 3{3}: 1HNMR (CDCl3, ppm): 8.1 (1H, m, Ar), 7.4 (2H, m, Ar), 6.4 (1H, m, Ar), 6.45 – 6.60 (2H, m, C-7 & C-8 double bond), 4.20 (1H, m, C-1), 2.80 – 3.30 (3H, m, C-3, C-4), 1.40 - 2.00 (4H, m, C-5, C-6). EIMS: 187.3 (M + 1), 188.4 (M + 2). 3{4}: 1HNMR (CDCl3, ppm): 8.23 (1H, m, Ar), 7.89 (1H, m, Ar), 7.11 (1H, m, Ar), 6.93 (1H, m, Ar), 6.50 (2H, m, C-7 & C-8 double bond), 4.52 (1H, m, C-1), 3.50 (1H, m, C-3), 3.30 (1H, m, C-3), 2.85 (1H, m, C-4), 1.40 – 2.15 (4H, m, C-5, C-6). EIMS: 187.3 (M + 1). 3{5}: 1HNMR (CDCl3, ppm): 7.20 – 7.70 (3H, m, Ar), 6.40-6.60 (2H, m, C-7 & C-8 double bond), 4.60 – 4.80 (1H, m, C-1), 3.35 (1H, m, C-3), 3.05 (1H, m, C-3), 2.75 (1H, m, C-4), 2.02 (1H, m, C-6), 1.66 (1H, m, C-6), 1.35 – 1.50 (2H, m, C-5). EIMS: 187.3 (M), 188.16 (M + 1). 3{6}: 1HNMR (CDCl3, ppm): 8.55 (1H, m, Ar), 8.05 (1H, m, Ar), 7.95 (1H, m, Ar), 7.60 (1H, m, Ar), 7.35 (1H, m, Ar), 6.70 (1H, m, Ar), 6.30-6.60 (2H, m, C-7 & C-8 double bond), 4.40 (1H, m, C-1), 3.80 (1H, m, C-3), 2.97 (1H, m, C-3), 2.77 (1H, m, C-4), 1.45 – 2.30 (4H, m, C-5, C-6). EIMS: 237.4 (M + 1), 238.3 (M+2).
Borne et al.
3{7}: 1HNMR (CDCl3, ppm): 8.27 (1H, m, Ar), 8.03 (1H, m, Ar), 7.51 (1H, m, Ar), 7.11 (1H, m, Ar), 6.46-6.68 (2H, m, C-7 & C-8 double bond), 4.56 (1H, m, C-1), 3.81 (1H, m, C-3), 3.09 (1H, m, C-3), 2.90 (1H, m, C-4), 2.31 (1H, m, C-6), 1.86 (1H, m, C-6), 1.60 (2H, m, C-5). EIMS: 373.0 (M + 1). 3{8}: 1HNMR (CDCl3, ppm): 8.55 (1H, m, Ar), (1H, m, Ar), 7.60 (1H, m, Ar), 7.40 (1H, m, Ar), 7.05 m, Ar), 6.46-6.58 (2H, m, C-7 & C-8 double bond), (1H, m, C-1), 3.43 (1H, m, C-3), 3.03 (1H, m, C-3), (1H, m, C-4), 2.17 (1H, m, C-6), 1.70 (1H, m, C-6), (2H, m, C-5). EIMS: 237 (M), 238 (M+1).
7.95 (1H, 4.68 2.88 1.50
Analysis of Products of General Structure 4 4{1}: 1HNMR (CDCl3, ppm): 8.10 (1H, m, Ar), 7.50 (1H, m, Ar), 6.48 (2H, m, Ar), 2.49-3.40 (3H, m, C-1, C-3), 1.45 – 2.01 (9H, m, C-4 – C-8). EIMS: 188.25 (M). anal. Cal. C, 76.55; H, 8.57; N, 14.88, found: C, 73.12; H, 7.95, N, 14.12 4{2}: 1HNMR (CDCl3, ppm): 8.24 (1H, m, Ar), 7.59 (1H, m, Ar), 6.23 (1H, m, Ar), 3.00 - 3.35 (3H, m, C-1, C-3), 1.50 – 2.00 (9H, m, C-4 - C-8). EIMS: 315.0 (M + 1). Anal. Cal: C, 45.88; H, 4.81; N, 8.92, found: C, 46.97; H, 4.34, N, 8.63 4{3}: 1HNMR (CDCl3, ppm): 8.05 – 8.50 (2H, m, Ar), 6.40-6.60 (2H, m, Ar), 2.80 – 3.50 (3H, m, C-1, C-3), 1.40 – 2.10 ((9H, m, C-4 – C-8). EIMS: 189.1 (M + 1). 4{4}: 1HNMR (CDCl3, ppm): 6.9 – 7.5 (4H, m, Ar), 3.30 – 3.65 (3H, m, C-1, C-3), 1.20 – 2.0 (9H, m, C-4 – C8). EIMS: 188.9 (M), 189.4 (M + 1), 190.3 (M + 2). Anal. Cal: C, 76.66; H, 8.57; N, 14.88, found: C, 73.36; H, 8.13, N, 13.31 4{5}: 1HNMR (CDCl3, ppm): 8.1 – 8.56 (3H, m, Ar), 3.20 – 3.70 (3H, m, C-1, C-3), 1.50-1.90 (9H, m, C-4 – C-8). EIMS: 188 (M + 1). Anal. Cal: C, 69.81; H, 7.99; N, 22.20, found: C, 66.62; H, 7.84, N, 20.82 4{6}: 1HNMR (CDCl3, ppm): 8.40 (1H, m, Ar), 8.15 (1H, m, Ar), 8.00 (1H, m, Ar), 7.60 (1H, m, Ar), 7.35 (1H, m, Ar), 6.60 (1H, m, Ar), 4.10 (1H, m, C-1), 3.60 (2H, m, C3), 1.65 – 2.20 (9H, m, C-4 – C-8). EIMS: 239.3 (M + 1), 240.4 (M+2). Anal. Cal: C, 80.63; H, 7.61; N, 11.75, found: C, 76.25; H, 7.91, N, 11.12 4{7}: 1HNMR (CDCl3, ppm): 8.5 (1H, m, Ar), 8.1 (1H, m, Ar), 7.8 (1H, m, Ar), 7.11 (1H, m, Ar), 4.30 (1H, m, C-1), 3.60 (1H, m, C-3), 3.13 (1H, m, C-3), 1.22 – 2.20 (9H, m, C4 – C-8). EIMS: 374.9 (M + 1), 375.9 (M + 2). Anal. Cal: C, 57.76; H, 4.31; N, 7.48, found: C, 58.23; H, 3.89, N, 7.38 4{8}: 1HNMR (CDCl3, ppm): 8.60 (1H, m, Ar), 7.90 (1H, m, Ar), 7.58 (1H, m, Ar), 7.36 (2H, m, Ar), 7.00 (1H, m, Ar3.98 (1H, m, C-1), 3.43 (2H, m, C-3), 1.2-2.1 (9H, m, C-4 - C-9). EIMS: 239 (M+1). Anal. Cal: C, 80.63; H, 7.61; N, 11.75, found: C, 78.78; H, 7.45, N, 11.04 REFERENCES [1]
Levi, M.S.; Khan, M.O.F.; Borne, R.F. Solution-phase parallel synthesis of N-substituted isoquinuclidines. Lett. Drug Design Discov., 2004, 1(4), 384-86.
Solution-Phase Synthesis of N-Arylisoquinuclidines [2] [3] [4] [5] [6] [7] [8] [9]
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