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Benzene rings as well as other aromatic systems abound among compounds used as therapeutic agents. The 60odd drugs described in this chapter represent a very small sample of the hundreds of agents that are centered on substituted benzene rings. These rings play manifold functions in drugs, ranging from simply providing simple steric bulk to forming an integral part of the pharmacophore. Most, but not all, of the drugs discussed in this chapter fall into the latter category and have been chosen for inclusion for their illustrative value. 2.1. ARYLETHANOLAMI NES One of the most reliable sources for leads for new drugs consists of the endogenous compounds that act as messengers for various vital functions. Epinephine (11), also known as adrenalin, and its Ndemethyl derivative norepinephrine (12), two closely related arylethanolamines that play a key role in homeostasis, were isolated and characterized structurally in the mid1930s. It was already recognized at the time that these two agents are intimately associated with the sympathetic branch of the involuntary, sometimes referred to as the autonomic nervous system. These com pounds, which, among other functions, transmit nerve signals across synapses in this system, play a key role in regulating blood pressure, heart rate, and constriction or dilation of bronchioles. The central role that adrenalin plays in this branch of the nervous system leads to its name as the adrenergic system.
CHAPTER 2 DRUGS BASED ON A SUBSTITUTED BENZENE RING Benzene rings as well as other aromatic systems abound among compounds used as therapeutic agents. The 60-odd drugs described in this chapter represent a very small sample of the hundreds of agents that are centered on substituted benzene rings. These rings play manifold functions in drugs, ranging from simply providing simple steric bulk to forming an integral part of the pharmacophore. Most, but not all, of the drugs discussed in this chapter fall into the latter category and have been chosen for inclusion for their illustrative value. 2.1. ARYLETHANOLAMINES One of the most reliable sources for leads for new drugs consists of the endogenous compounds that act as messengers for various vital functions. Epinephine (1-1), also known as adrenalin, and its N-demethyl derivative norepinephrine (1-2), two closely related arylethanolamines that play a key role in homeostasis, were isolated and characterized structurally in the mid-1930s. It was already recognized at the time that these two agents are intimately associated with the sympathetic branch of the involuntary, sometimes referred to as the autonomic nervous system. These com- pounds, which, among other functions, transmit nerve signals across synapses in this system, play a key role in regulating blood pressure, heart rate, and constriction or dilation of bronchioles. The central role that adrenalin plays in this branch of the nervous system leads to its name as the adrenergic system. Strategies for Organic Drug Synthesis and Design, Second Edition. By Daniel Lednicer Copyright # 2009 John Wiley & Sons, Inc. 43 Epinephrine is often one of the first drugs used in treating trauma because of its cardiostimulant and bronchodilating actions. Simple replacement of the methyl group on nitrogen by isopropyl gives isoproterenol (2-3), a drug with a longer duration of action. Each of these drugs is available in racemic form by a relatively short, straight- forward synthesis. Friedel–Crafts acylation of catechol with chloroacetyl chloride leads to the chloroketone (2-1). Displacement of halogen with isopropylamine gives aminoketone (2-2); hydrogenation over platinum reduces the carbonyl group to give racemic isproterenol (2-3). The same sequence using methylamine leads to epinephrine, and resolution of this last as its tartrate salt gives l-epinephrine (1-1) identical to the natural product [1]. The isomer of (2-3) in which both phenolic hydroxyl groups occupy the meta position, metaproterenol (3-5), retains the bronchodilating activity of the isoproter- onol. The synthesis begins with treatment of substituted acetophenone (3-1) with sel- enium dioxide; the methyl group is thus oxidized to the corresponding aldehyde to give glyoxal (3-2). Reductive amination with isopropylamine can be envisaged to proceed first through the imine (3-3). Hydrogen then reduces that function to the secondary amine. The carbonyl group is reduced in the process to give aminoalcohol (3-4). The phenolic methyl ethers are then cleaved by means of hydrogen bromide to give metaproterenol (3-5) [2]. 44 DRUGS BASED ON A SUBSTITUTED BENZENE RING The adrenergic nervous system is itself divided into two broad categories, denoted as the a and b branches. Drugs such as metaproteronol and deterenol, a congener of isoproterenol lacking the meta hydroxyl group, act largely as b-adrenergic agonists. The fact that the proton in a sulfonylanilide should have a pK in the same range as a phenol encouraged the preparation of the deterenol congener sotalol (4-4). It is of note that though this compound interacts with b-adrenergic receptors, it does so as an antagonist. This compound was in fact one of the first b-blockers. One of several routes to this compound starts with the reduction of readily available para-nitroacetophenone (4-1) to the correspond- ing aniline (4-2) by a method specific to nitro groups such as iron and hydrochloric acid. Reaction with methanesulfonyl chloride gives the sulfonanilide (4-3). This intermediate is then carried on to sotalol (4-4) by the same series of reactions used to prepare isoproterenol. The history of drug discovery aptly illustrates the important role played in this process by serendipity. Clinical investigations on sotalol revealed that the agent had pronounced activity as an antiarrhythmic agent, an action that could be, and was, logically attributed to the compound’s b-blocking action. The observation that both enantiomers seemed to have equal potency, however, cast some doubt on this explanation for the antiarrhythmic activity. Subsequent work, perhaps spurred by this discrepancy, had in fact shown that sulfonanilides, which lack the 2.1. ARYLETHANOLAMINES 45 phenethanolamine side chain, show quite good antiarrhythmic activity in their own right. This observation has led to a series of antiarrhythmic agents whose structures have in common only a sulfonamide group. The first of these agents, ibutilide (5-3), incorporates a vestige of the ethanolamine side chain, in the form of a 1,4-aminoalcohol. Preparation starts with the Friedel–Crafts acy- lation of methanesulfonylanilide with succinic anhydride to give the keto-acid (5-1). Reaction of the corresponding acid chloride with N-ethyl-N-heptylamine gives the amide (5-2). Reaction with lithium aluminum hydride in the cold serves to reduce both the amide and ketone to afford ibutilide [3]. Further work shows that activity is retained when the hydroxyl group is replaced by polar groups such as an amide or even a non-enolizable sulfonamide. Ester interchange of the mesylate from ethyl para-aminobezoate with N,N-diethyl- ethylenediamine gives the antiarrhythmic agent sematilide [4] (5-5). In a similar vein, reaction of sulfonyl chloride (5-6) (from reaction of methanesulfonylanilide and chlorosulfonic acid), with N,N 0 -di-iso-propylethylenediamine gives risotilide (5-7) [5]. A more recent example, which involves an enantiomerically pure compound, reverts to the original lead by incorporating a hydroxyl group on the benzylic carbon. Preparation of this close relative of ibutilide (5-3) uses the same starting material. Acylation of n-dibutylamine with the acid chloride from the treatment of (6-1) with tert-butylcarbonyloxy chloride leads to the amide (6-2). Reduction of the carbonyl group in this compound with chloro-(þ)-diisopropylcamphemyl borane (DIPCl) proceeds to afford the R alcohol (6-3) in high enantiomeric exess. 46 DRUGS BASED ON A SUBSTITUTED BENZENE RING Reduction of the amide function with lithium aluminum hydride then reduces the amide carbonyl to afford atilide (6-4) [6]. Antiarrhythmic activity is interestingly maintained in a compound whose structure does not bear the slightest resemblance to adrenergic agents. Alkyation of N-methyl-4-nitrophenethylamine (7-2) with chloroethyl ether (7-1) leads to the tertiary amine (7-3). The nitro group is reduced by any of several methods to afford aniline (7-4). Acylation of the newly formed amino group with methanesulfonyl chloiide affords the antiarrhythmic agent dofetilide (7-5) [7]. The b-adrenergic system is itself further divided into several branches; receptors for these subsystems show different ligand structural preferences. The cardio- vascular system is responsive largely to b 1 -adrenergic agents; activation leads to increases in blood pressure and heart rate. Bronchioles constitute an important target for b 2 -adrenergic agonists; activation leads to relaxation and resolution of bronchospasms. Use of the classical b agonist isoproterenol (2-3) for the treatment of asthma is limited by the side effect due to poor selectivity for b 2 receptors. 2.1. ARYLETHANOLAMINES 47 Compounds that exhibit preferential b 2 -adrenergic agonist activity have proven to be very useful in the treatment of asthma. The compounds discussed below represent only a very small selection from the dozens of antiasthma compounds that have been investigated in the clinic. It is of interest to note that while the replacement of the para hydroxyl of a phenylethanolamine by sulfonanilido as in sotalol (2-4) leads to an antagonist, the corresponding change at the meta position in this series leads to an adrenergic agonist that shows selectivity for b 2 receptors. The synthesis of this agent, soterenol (8-6), starts with the nitration of p-benzyloxyacetophenone. Reduction of the intermediate nitro compound (8-2) with hydrazine in the presence of Raney nickel gives the corresponding aniline (8-3). This is then converted to the sulfonamide (8-4), by reaction with methane- sulfonyl chloride. Bromination of the methyl group of the ketone followed by dis- placement with isopropylamine leads to the intermediate (8-5). Reduction of the ketone to an alcohol followed by hydrogenolysis of the benzyl protecting group affords soterenol (8-6) [8]. A simple aliphatic alcohol at the meta position is actually sufficient for conferring b 2 agonist activity to a phenolethanolamine as demonstrated by the very widely used drug albuterol (9-4), formerly known as salbutamol. The product (9-1) from the acetylation of methyl salicylate provides the starting material. The usual amination sequence using tertiary-butylbenzylamine gives the correspond- ing aminoketone (9-2). Reduction by means of lithium aluminum hydride converts the ester to a carbinol and the ketone to the requisite alcohol in a single step. The benzyl protecting group is then removed by catalytic reduction to afford albuterol (9-4) [9]. 48 DRUGS BASED ON A SUBSTITUTED BENZENE RING The analogue (10-5) of albuterol in which the amino group is primary (10-1)pro- vides the starting material for a significantly more lipophilic b agonist. Construction of the side chain for this compound involves mono-alkylation of 1,6-dibromohexane (10-4) with 2-phenylethanol to give bromide (10-2). Alkylation of (10-1) with that halide gives salmeterol (10-5) in a single step [10]. 2.1. ARYLETHANOLAMINES 49 A selective b 2 agonist is retained when the phenol at the meta position is replaced by a urea group. Sequential reactions of the soterenol intermediate (11-1) with phosgene and then ammonia lead to urea (11-2). The by-now familiar bromination– amination sequence gives the aminoketone (11-3). The ketone is then reduced to an alcohol with a sodium borohydride and the benzyl protecting group is removed by hydrogenolysis to give carbuterol (11-4) [11]. The activity of b-blockers as antihypertensive agents is discussed in greater detail in the section that follows; it is, however, relevant for the discussion at hand to note that some of the shortcomings of those drugs can to some extent be overcome by incorporating a degree of a-adrenergic blocking activity into the compound. The prototype-combined a/b-blocker, labetolol (12-6), incorporates an amide group on the phenylethanolamine moiety reminiscent of the urea on carbuterol. Friedel– Crafts acetylation of salicilamide (12-1) gives substituted acetophenone (12-2); this is then converted to bromoketone (12-3). Use of that intermediate to alkylate 4-phe- nylbultyl-2-amine (12-4) gives the aminoketone (12-5). The ketone is then reduced to an alcohol by catalytic hydrogenation [12]. The resulting compound, labetolol (12-6), consists of a mixture of two diastereomers as a consequence of the presence of two chiral centers. 50 DRUGS BASED ON A SUBSTITUTED BENZENE RING The discovery of a third subset of adrenergic binding sites, the b 3 -receptors, has led to a compound that provides an alternate method to currently available anti- cholinergic agents for treating overactive bladders. There is some evidence, too, that b 3 agonists may have some utility in treating Type II diabetes. Synthesis of the compound begins with the construction of the biphenyl moiety. Thus, conden- sation of methyl meta-bromobenzoate (13-1) with meta-nitrophenylboronic acid (13-2) in the presence of palladium tetrakistriphenylphosphine leads to the coupling product (13-3). The nitro group is then reduced to the corresponding amine (13-4). Alkylation of this with the t-BOC protected 2-bromoethylamine (13-5) leads to the intermediate (13-6). Treatment with acid removes the protecting group to give the primary amine (13-7). Condensation of this last product with meta-chlorostyrene oxide leads to the formation of solabegron (13-9), a molecule that incorporates the aryl ethanolamine moiety present in the great majority of compounds that act on adrenergic receptors [13]. 2.1. ARYLETHANOLAMINES 51 An agent that acts on a subset of adrenergic a-receptors, specifically alpha- 1A/1L receptors, has also shown activity on the same clinical endpoint. The synthesis starts with Mitsonobu alkylation of the nitrophenol (14-1)hN-trityl protected imidazole methylcarbinol (14-2) to give the ether (14-3). The nitro group on the benzene ring is then reduced to the primary amine by any of several methods (14-4). The resulting aniline is then converted to the correspond- ing sulfonamide (14-5) reaction with methanesulfonyl chloride. Hydrolysis with mild acid then removes the trityl protecting group to afford dabuzalgron (14-6) [14]. Chloramphenicol (15-6), which can formally be classified as a phenylethanola- mine derivative, exhibits far different activity from the other compounds endowed with that structural feature. This compound actually comprised one of the first orally active antibacterial agents. The one-time extensive use of this drug declined with the recognition of its propensity to cause blood discrasias and the availability of safer alternatives. The compound is, however, still in wide use as a topical antibac- terial agent. The relatively simple structure of this product from Streptomyces vene- zuela fermentation, initially known as chloromycetin, led early on to its production by total synthesis. The comparatively short and straightforward route pre- sented in the first synthesis does, however, suffer from a lack of steric control. The first step in the synthesis consists of aldol condensation of benzaldehyde with 2- nitroethanol to give a mixture of all four enantiomers of nitropropanediol (15-1); the total mixture is reduced catalytically to the corresponding mixture of aminodiols (15-2). The threo isomer is then separated by crystallization and resolved as a dia- steromeric salt to give the D(2) isomer. Acylation with dichloroacetyl chloride initially gives the triacetate, and saponification gives the desired product (15-3). The free hydroxyls are then converted to the acetates by means of acetic anhydride and the resulting product (15-4) nitrated with the traditional nitric–sulfuric acid mixture (15-5). Saponification then removes the acetate protecting groups and affords chloramphenicol (15-6). 52 DRUGS BASED ON A SUBSTITUTED BENZENE RING [...]... under reaction conditions to afford (36-5) Base catalyzed of that product with rhodanine (36-6) leads to aldol condensation to afford (36-7) Catalytic hydrogenation then reduces the double bond to afford the antidiabetic agent darglitazone (36-8) [37] 68 DRUGS BASED ON A SUBSTITUTED BENZENE RING Chromanol (37-1), which in essence comprises a cyclic acetal of 3-hydroxypropylbenzaldehyde, is available... avoids the use of a base for saponifying the intermediate urethane Thus, reaction of (23 -3) with trichloroethyl formate leads to the N-demethylated chlorinated urethane (23 -4) Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23 -5) [23 ] 60 DRUGS BASED ON A SUBSTITUTED BENZENE RING N-demethylation is a well-recognized drug... dioxide to afford an acid (37-4) on workup This acid is then resolved by separating the diastereomeric salts formed with a chiral base The acid from the desired form is then reduced to afford the aldehyde (37-5) as a single enantiomer Aldol condensation with rhodanine (36-6) 2. 3 ARYLSULFONIC ACID DERIVATIVES 69 followed by reduction of the double bond in the first product then affords englitazone (37-6)... resemblance to para-aminobenzoic acid Treatment of chlorobenzene with chlorosulfonic acid under forcing conditions leads to the meta disubstituted sulfonyl chloride (29 -1); ammonolysis of that intermediate leads to the diuretic agent chlorphenamide (29 -2) [27 ] In a similar vein, ortho-chlorophenol (29 -3) yields bis-sulfonamide (29 -4) on sequential reaction with chlorosulfonic acid and ammonia Hydroxyl groups... 66 DRUGS BASED ON A SUBSTITUTED BENZENE RING sulfonyl-bearing benzene ring led to orders of magnitude increases in potency (This was memorialized by the Upjohn trade name Micronasew for glyburide.) Reaction of the acetamide (33-1) from 2- phenethylamine with chlorosulfonic acid results in the formation of the para sulfonyl chloride; ammonolysis of that intermediate followed by base- catalyzed removal... Wilgerodt reaction constitutes the key to the preparation of ibufenac Thus, reaction of the acetylation product ( 42- 1) from isobutyl benzene and acetyl chloride with sulfur and morpholine leads to the transposition of the oxidized function to the terminal carbon and formation of thiomorpholide ( 42- 2) Hydrolysis of the thioamide 72 DRUGS BASED ON A SUBSTITUTED BENZENE RING in acid results in the concomitant... presumably recognizes the acidic sulfonamide proton as a carboxylate hydrogen Incorporation of the misconstrued sulfa drugs brings folate synthesis to a halt The rather strict structural requirements in this class of antibacterial agents directly reflect the mode of action: The presence of a primary aniline group and at least one sulfonamide proton are mandatory for activity; additional substituents on. .. enantiomer [15] 54 DRUGS BASED ON A SUBSTITUTED BENZENE RING 2. 2 ARYLOXYPROPANOLAMINES 2. 2.1 b-Blockers The discovery that b-sympathetic blocking agents, for example sotalol, seemed to have useful clinical activity in treating the symptoms of cardiovascular disease such as angina and arrhythmias engendered considerable interest in this class of agents The finding that b-blocking activity was retained... antibacterial drugs The first of the many available synthetic antibacterial agents available today was in fact discovered due to a set of adventitious events Intrigued by the observation that certain organic dyes showed strong affinity for specific bacteria, Domagk and his collaborator Klarer in the early 1930s in Germany initiated a synthesis and screening program to test the antibacterial action of... electrocyclic rearrangement related conceptually to the little-known Hauser ortho substitution rearrangement The simplest example of the latter depends on the formation of a carbanion by abstraction of one of the acidic protons from a benzyltrimethyl quaternary salt to give I (the 74 DRUGS BASED ON A SUBSTITUTED BENZENE RING abstraction of a more acidic benzyl proton gives a stable anion that simply reverts . CHAPTER 2 DRUGS BASED ON A SUBSTITUTED BENZENE RING Benzene rings as well as other aromatic systems abound among compounds used as therapeutic agents. The 60-odd drugs described in this chapter. displaced by any one of several methods to afford the primary amine and thus fluvoxamine (25 -4) [25 ]. 60 DRUGS BASED ON A SUBSTITUTED BENZENE RING 2. 3. ARYLSULFONIC ACID DERIVATIVES 2. 3.1. Antibacterial. activation leads to increases in blood pressure and heart rate. Bronchioles constitute an important target for b 2 -adrenergic agonists; activation leads to relaxation and resolution of bronchospasms.