J. Med. Chem. 1982,25, 670-679
`670
`24 (1,4-Benzodioxan-2-yl)methyl]imidazole Hydrochloride
`(10). To a mixture of 35 g (200 mmol) of 4,16a,b 14 g of ethanol,
`and 100 mL of diethyl ether was added 12 g of HC1 gas. The flask
`containing the mixture was tightly stoppered and left at 5 "C for
`4 days, at which time the solid imidate hydrochloride 7 was
`isolated by filtration. After the solid was washed with diethyl
`ether, there was obtained 35 g (-68%), which was used without
`further purification. A mixture of 35 g (136 mmol) of 7, 19.91
`g (183 mmol) of aminoacetaldehyde diethyl acetal, and 450 mL
`of ethanol was heated at reflux for 18 h. Evaporation of excess
`solvent left 61.6 g of an oily residue. This residue was mixed with
`600 mL of 4 N HCl, and the mixture was stirred at 60 "C for 24
`h. The mixture was filtered to remove a small amount of solid,
`and the filtrate was extracted with dichloromethane. The aqueous
`layer was basified with scdium hydroxide and thoroughly extracted
`with dichloromethane. Evaporation of solvent left a residue, which
`was filtered through 70 g of 70-230 mesh silica gel with 500 mL
`of 10% methanol-ethyl acetate. Evaporation of the filtrate left
`an oil. This material was taken up in 70 mL of 2-propanol, and
`an HC1 salt was made by passing HC1 gas into the solution. The
`salt was collected by filtration and was washed with diethyl ether:
`13C NMR (Me2SO-d6) 6 27.9 (t), 67.1 (t), 70.9 (d), 118.0 (d), 118.3
`(d), 119.9 (d), 123.1 (d), 123.3 (d), 142.6 (s), 143.2 (s), 143.5 (8).
`Anal. (Cl2HI3C1N2O2) C, H, N, C1.
`1-Et hyl-2- [ (1,4-benzodioxan-2-yl)met hyllimidazole Hy-
`drochloride (13). To a solution of 75 g (347 mmol) of 10 in 250
`mL of DMF at 0 "C was added 20 g (41.6 mmol) of 50% sodium
`hydride in mineral oil in two equal portions. After 30 min at room
`temperature, 56.8 g (364 mmol) of ethyl iodide was added dropwise
`
`over 15 min at 0 "C. The mixture was then stirred for 30 min
`at room temperature. The mixture was poured into 700 mL of
`water, and the resulting mixture was extracted with three 200-mL
`portions of ethyl acetate. The combined extract was washed with
`100 mL of water and then with two 250-mL portions of 5% HC1
`solution. The combined acid extract was washed with 100 mL
`of ethyl acetate and then made basic and concentrated ammonium
`hydroxide. The product was extracted with two 200-mL portions
`of ethyl acetate. Evaporation of solvent gave an oil, which was
`filtered through 100 g of 70-230 mesh silica gel with 500 mL of
`ethyl acetate. Evaporation of the filtrate gave 58.1 g of an off-white
`solid mp 78-79 "C; NMR (CDCl,) 6 1.35 (d, 2 H, J = 7 Hz), 3.05
`(d, 2 H, J = 6 Hz), 3.72-4.85 (m, 5 H), 6.7-7.33 (m, 6 H).
`The hydrochloride salt was prepared by passing excess HCl
`gas into a methanol solution of 13, followed by precipitation with
`diethyl ether, mp 174-175 "C. Anal. (C14H17C1N202) C, H, N.
`2-[ (1,4-Benzodioxan-2-yl)met hyl]benzimidazole Hydro-
`chloride (22). A mixture of 5 g (19.4 mmol) of 7,2.16 g (20 m o l )
`of o-phenylenediamine, and 50 mL of ethanol was heated at reflux
`for 18 h. The solvent was evaporated, and the residue was sus-
`pended in 150 mL of 5% ammonium hydroxide. The product
`was extracted into ethyl acetate. Evaporation of the ethyl acetate
`gave an oil. The hydrochloride salt was prepared by passing excess
`HC1 into a methanol solution of 22, followed by precipitation with
`diethyl ether: 13C NMR (CD30D-D20) 6 29.14 (t), 67.40 (t), 70.98
`(d), 114.44 (d), 117.85 (d), 117.98 (d), 122.89 (d), 127.05 (d), 131.83
`(e), 142.69 (s), 143.31 (s), 150.14 (9). Anal. (Cl6Hl5C1N2O2) c,
`H, N.
`Acknowledgment. We thank Paul Cheung for log D
`determinations and Dr. Michael Maddox, Ms. Janis Nel-
`son, and Ms. Lilia Kurz for analytical assistance.
`
`(30) Arunlakshana, 0.; Schild, H. 0. Br. J. Pharmacol. 1959,14,48.
`
`Arylethanolamines Derived from Salicylamide with a- and P- Adrenoceptor
`Blocking Activities. Preparation of Labetalol, Its Enantiomers, and Related
`Salic ylamides
`
`James E. Clifton, Ian Collins, Peter Hallett, David Hartley, Lawrence H. C. Lunts,* and Philip D. Wicks
`Chemistry Department, Glaxo Group Research Ltd., Ware, Hertfordshire, SG12 OD England. Received August 20, 1981
`
`A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess p-adrenergic blocking
`properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked
`a-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man,
`and syntheses of its four stereoisomers are described. The enantiomer 90 with the R c o n f i a t i o n at both asymmetric
`centers possessed most of the P-blocking activity but little a-blocking activity. That with the S configuration at
`the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an a-adrenoceptor blocking
`agent.
`
`In a previous publication' we reported the preparation
`of the saligenins 2 from the salicyl esters 1 t o give potent
`fH2Ph
`
`3
`
`H2NOC
`
`H O
`
`2, X = HOCH,
`3, X = R'NHCO
`m /y
`
`C H (0 H ! C H,N H Me(C H,
`
`)2
`
`34, Y = H
`53, Y = 3,4-(-OCHZ0-)
`
`(1) D. T. Collin, D. Hartley, D. Jack, L. H. C. Lunts, J. C. Press,
`and P. Toon, J. Med. Chem., 13, 674 (1970).
`
`&-adrenoceptor stimulants. In an extension of this work,
`aimed at investigating the effect of analogous structures
`on adrenergic activity, we converted the esters 1 into the
`corresponding amides 3 and found t h a t they blocked 6-
`adrenoceptors.2 Furthermore, when these amides were
`substituted on the basic nitrogen atom with specific aralkyl
`groups, the products possessed, in addition, a-adrenoceptor
`blocking activity and a capacity to produce rapid and
`long-lasting falls in blood pressure in the rat and dog.3
`This article describes a series of analogues 3 and the de-
`velopment of a novel antihypertensive agent, labetalol(34),
`operating by antagonism of a-adrenoceptors in which side
`effects, such as reflex tachycardia, are minimized by the
`concomitant antagonism of cardiac ,8-adrenoceptors. The
`biological activity of labetalol has been extensively re-
`viewed.*+
`
`(2) L. H. C. Lunts, P. Toon, and D. T. Collin, U. K: Patent
`1 200 886 (1970).
`(3) L. H. C. Lunts and D. T. Collin, U.K. Patent 1266058 (1972).
`
`0022-2623/82/1825-0670$01.25/0 0 1982 American Chemical Society
`
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`
`Arylethanolamines Derived from Salicylamide
`
`Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6 671
`
`Scheme I
`
`method A Meo2cB
`
`c H o H c H R'N/
`
`R 4
`
`\R3
`
`R h H p
`
`R'NHOC
`
`/ W h
`CHOHCHR N
`\ R 3
`
`HO
`
`( R 4 = P h C H p )
`
`HO
`
`-
`
`R'NHOC
`
`He, Pd/C
`
`CHOHCH R'NHR
`
`R'NHOC
`
`COCHR'N(CH,Ph
`
`)2
`
`HO
`
`method E
`
`HO
`
`Y p , P d / P t / C
`
`t
`'R3 EfcocHR
`Meo2cm
`
`method F
`
`I
`
`CHOHCHR'NH,
`
`R' " O
`HO
`
`C
`
`m
`
`
`
`H2, P d / P t / C
`
`, ,CVh
`
`CH OH CH,N H R3
`
`/%Ph
`2
`COCHR N
`'R3
`
`I R'NHz
`II Hp, P d / P t / C
`method C
`
`HO
`
`R'NHOC
`
`C O C H R ~ E ~
`Ph CHzNHR'
`method D
`
`-
`
`R'NHOC
`
`HO
`HO
`Table I. 5 4 2-Amino-1-hydroxyethy1)salicylic Acid Esters a
`
`HO
`
`yield,
`method
`formula
`R3
`no.
`mp, "C
`%
`EC
`C,oH,,FNO,~HCl
`2-FC6H,( CH, ), CHMe
`4
`139-143
`76
`5
`EC
`C,, H,, FNO ,.HCl
`4-FC,H,(CH,),CHMe
`159-1 63
`7 5
`3,4-(CH,O2)C,H3(CH,),CHMe C,, H,,N06*HC1
`EC
`6
`187-191
`93
`EC
`4-AcNHC6H,( CH,),CHMe
`e 2 2 H2J2OS
`7
`1 0 5
`51
`PhCO(CH,),
`C,,H,, NO,*HCl
`8
`165-167
`34
`d
`9
`PhCHOH( CH,),
`e
`145-148
`28
`CL9H23N0
`F f
`PhCH,CH( C0,Et)CHMe
`C,,H,, NO ,*HCl
`10
`176-177
`6 5
`EC
`C,,H,,N,O,
`PhCONH-(4-c-C5H,N)-CH,CHMe
`1 1
`157-162
`51
`Me-Ea
`84
`EC
`PhNHCH,CHMe
`C,,H,,N20,*2HC1
`1 2
`183-185
`Et
`EC
`PhNHCOCH, CHMe
`13
`124-1 28
`57
`C20H24N205
`a For analogous esters not described in this table, see ref 1. A1 = EtOH; B = PhH; Ea = EtOAc; Et = Et,O; Ip = i-PrOH;
`Me = MeOH; Pe = petroleum ether (bp 60-80 "C).
`Reductive alkylation of the N,N-dibenzylglycyl ester (Scheme I).
`See Experimental Section. e Reduction of 8 with NaBH,.
`f Reductive alkylation of the primary amine ester (Scheme I).
`
`crystn
`solvent b
`Ea-Pe
`Me-Ea
`Ea-Pe
`Ea-Pe
`IP
`Ea
`Ea-Pe
`
`5
`
`Table 11. 5-( N-Substituted-glycy1)salicylamides
`
`R'NHCO
`
`HO
`
`,CH,Ph
`COCHzN
`'R3
`
`R3
`R'
`no.
`Me, CH
`H
`1 4
`H
`15
`PliCH,
`Me,CH
`Me
`1 6
`Me,C
`H
`17
`Ph( CH,),CHMe
`H
`1 8
`(I See footnote b to Table I.
`Lately, other phenethanolamines have been shown to
`combine ,f3-adrenoceptor blocking activity with a-blocking
`and one of our analogues,
`or vasodilating
`
`formula
`C,,H,,N,O,.HCl
`C23H22N203
`C,,H,,N,03*HC1
`C,oH,,N,03*HCl
`C26H28N203
`
`(4) R. T. Brittain, D. M. Harris, D. Jack, and D. A. Richards,
`Pharmacol. Biochem. Prop. Drug Subst., 2, 299 (1979).
`(5) R. T. Brittain and G. P. Levy, Br. J. Clin. Pharmacol., 3
`(Suppl), 681 (1976).
`(6) R. N. Brogden, R. C. Heel, T. M. Speight, and E. S. Avery,
`Drugs, 15, 251 (1978).
`(7) K. Imai, K. Niigata, T. Fujikura, S. Hashimoto, and T. Take-
`naka, Japanese Patent 79 61139 (1979); Chem. Abstr., 92,
`2 2 2 8 3 ~ (1980). Yamanouchi Pharmaceutical Co. Ltd., Japa-
`nese Patent 8053261 (1980); Chem. Abstr., 94, 46962 (1981).
`
`method
`C
`D
`C
`C
`D
`
`yield,
`%
`77
`53
`6 4
`80
`6 8
`
`crystn
`solvent a
`Me
`Ea
`AI-Ea
`Me
`IP
`
`mp, "C
`216-218
`179-180
`205-209
`230 dec
`116-120
`
`medroxalol(53), has been the subject of detailed biological
`investigation.8 In addition, other @-adrenergic agents that
`induce a fall in peripheral resistance without reflex tach-
`
`(8) (a) J. M. Grisar, G. P. Claxton, T. M. Bare, R. C. Dage, H. C.
`Cheng, and J. K. Woodward, J. Med. Chem., 24, 327 (1981).
`(b) H. C. Cheng, 0. K. Reavis, Jr., J. M. Grisar, G. P. Claxton,
`D. L. Weiner, and J. K. Woodward, Life Sci., 27, 2529 (1980).
`(c) R. C. Dage, H. C. Cheng, and J. K. Woodward, J. Cardio-
`uasc. Pharmacol., 3, 299 (1981).
`(9) R. E. Philion, D. K. Phillips, S. C. Laskowski, D. C. Schlegel,
`R. R. Lorenz, P. H. Hernandez, and H. E. Lape, "Abstracts of
`Papers", 176th National Meeting of the American Chemical
`Society, Miami Beach, FL, Sept 1978, American Chemical
`Society, Washington, DC, 1978, Abstr MEDI 024.
`
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`
`672 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6
`
`Table 111. ( 2-Amino-1-hydroxyethy1)salicylamides
`
`Clifton et al.
`
`formula
`
`C1’3H24N203
`C,,H,,N,O,*HCl
`
`method
`A
`A
`
`yield,
`%
`53
`65
`
`crystn
`solventa
`B
`
`mp, “ C
`155-156
`183-185
`
`position
`of side
`chain
`4
`5
`
`R3
`R’
`no.
`Me,CH
`H
`19
`Ph( CH,),CHMe
`Me
`20
`a See footnote b to Table 1.
`ycardia have been reported, e.g., prizidolol,1° MK-761,11
`and bucindolol;12 these compounds, however, are aryl-
`oxypropanolamines.
`Chemistry. The amides 3 were generally prepared from
`the corresponding esters l1 by treatment with a methanolic
`solution of the appropriate amine or ammonium hydroxide
`at room temperature, followed by removal of any benzyl
`group by catalytic hydrogenation (Scheme I, methods A
`and B). This procedure was preferable to aminolysis of
`the intermediate glycyl esters, followed by hydrogenation
`(method C). A less flexible but otherwise satisfactory route
`involved the reaction of 5-(bromoacety1)salicylamide with
`an N-benzylamine, followed by catalytic reduction of the
`ketone and removal of the N-benzyl group (method D).
`The substituent R3 could also be introduced by reductive
`alkylation of dibenzylamino ketones (method E) or pri-
`mary arylethanolamines (method F) with the appropriate
`carbonyl compound. Amides obtained by these routes are
`listed in Tables 11-IV.
`Since aminolyses of the phenolic ester 1 did not readily
`afford a hydroxamic acid 26 or a 2-hydroxyethyl amide 25,
`these were prepared from the benzyloxy ester 73 with
`hydroxylamine and 2-aminoethanol, respectively, followed
`by hydrogenolysis of both benzyl protecting groups.
`,CH,Ph
`
`M e O 2 C W C H O H C H 2 N ‘
`
`PhCH20 w
`
`*HCI
`‘ C H M ~ ~
`
`73
`Phenethanolamine esters were made by the method
`previously described;l new compounds are shown in Table
`I.
`
`The 4-substituted salicylamides were much less acces-
`sible, and only the isopropylamino derivative 74 was pre-
`pared from the corresponding benzylamino ester 75l by
`method A.
`
`74, X = H,NOC; R4 = H
`75, X = Me0,C; R4 = CH,Ph
`Hitherto unreported ketones used in the reductive al-
`kylation of amines (methods E and F) are listed in Table
`V. They were prepared either by catalytic reduction of
`
`(10) A. Bell, M. J. Boyce, W. I. Burland, and D. D. Underwood, Br.
`J. Clin. Pharrnacol., 9, 299P (1980).
`(11) J. J. Baldwin, W. C. Lumma, G. F. Lundell, G. S. Ponticello,
`A. W. Raab, E. L. Engelhardt, R. Hirschmann, C. S. Sweet,
`and A. Scriabine, J. Med. Chem., 22, 1284 (1979).
`(12) J. Am. Med. Assoc., 242, 2467 (1979).
`
`an unsaturated ketone (method G) or by alkylation of an
`amine or phenoxide with chloroacetone (method H).
`HP, W C
`ArCH=CHCOMe
`ArCH2CH2COMe
`ArOH + ClCH2COMe
`ArOCH2COMe
`XNH + C1CH2COMe
`XNCHzCOMe
`X = ArMe or heterocyclyl residue
`Representative examples are given under Experimental
`Section.
`When the substituent R3 was asymmetric, the products
`usually contained approximately 50% of each racemic pair
`of diastereoisomers. Their ratio could be assessed from
`the NMR spectra of their hydrochlorides. When deter-
`mined in an isotropic solvent such as pyridine, two
`doublets due to the methyl group were observed at T 9.02;
`these doublets were separated by 1 Hz using a 60-MHz
`spectrometer.
`One compound, labetalol (34), was selected for devel-
`opment as an antihypertensive agent4 and is now marketed
`as Trandate.
`Stereochemistry. Labetalol(34) contains two asym-
`metric centers and, therefore, consists of two racemic
`compounds. The method of preparation of labetalol hy-
`drochloride (method D) and its crystallization from etha-
`nol-ethyl acetate consistently provided material with a mp
`of 188-191 “C. This product was a 5050 mixture of the
`two components as assessed by NMR spectra in pyridine,
`by GLC,13 and by HPLC. Under carefully controlled
`conditions, it was possible to separate these racemic sub-
`stances by fractional crystallization. Crystallization of the
`hydrochloride six times from ethanol gave “racemate I
`hydrochloride”, mp 220 “C, whereas “racemate 11” was
`preferentially obtained by four recrystallizations of labe-
`talol base from ethanol, followed by conversion into the
`hydrochloride, mp 183 “C. Comparison of these two ra-
`cemic modifications with labetalol (Table IV) showed that
`the a-blocking activity resided mainly in “racemate I”,
`whereas the /?-blocking activity is due almost entirely to
`“racemate 11”. These results have been confirmed in a
`recent p~b1ication.l~
`In order to correlate the biological activity with stereo-
`chemical structure, we synthesized the four individual
` enantiomer^.'^ This required the preparation of the R and
`S forms16 of 1-methyl-3-phenylpropanamine and their
`conversion into the corresponding mixtures of diastereo-
`
`(13) G. Munro, J. H. Hunt, L. R. Rowe, and M. B. Evans, Chro-
`matographia, 11, 440 (1978).
`(14) Y. Nakagawa, N. Shimamoto, M. Nakozawa, and S. Imai, Jpn.
`J. Pharmacol., 30, 743 (1980).
`(15) Since this work was completed a synthesis of these enantiom-
`ers has been disclosed: E. H. Gold and W. Chang, Eur. Pat.
`Appl. 9702 (1980).
`(16) R. S. Cahn, C. K. Ingold, and V. Prelog, Experientia, 12, 81
`(1956).
`
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`
`Arylethanolamines Derived from Salicylamide
`
`Scheme I1
`M e
`
`H
`
`84, R R (90%)
`60% Pd, Hz,50 psi
`
`I
`
`H
`
`,Me
`
`H2N
`
`P h
`
`86, R
`H M e
`
`‘CHZPh
`88
`
`Ph
`85, RS (10%)
`
`H Me -
`PhCHO -
`
`Pl-H2,
`
`PhCHZNH
`87, R
`
`Ph
`
`H Me
`
`t?
`
`-OH
`89, SR (50%)
`H Me
`
`A r
`
`HzNcom
`
`90, R R (50%)
`
`a & =
`
`Ph
`
`HO
`mers of labetalol according to method D.
`The (R)-amine 86 was prepared by asymmetric synthesis
`in a manner similar to that used to prepare some optically
`active amphetamine derivatives (Scheme II).l’ Com-
`mercially available (R)-(+)-a-methylbenzylamine 83 was
`reductively alkylated with 4-phenyl-2-butanone and hy-
`drogen over Raney nickel catalyst at 50 psi to give a
`mixture containing the (RE)-amine 84 and the (RS)-amine
`85 in a ratio of 9:l. This mixture was converted into the
`corresponding hydrochlorides and recrystallized twice from
`methanol-ethyl acetate to give the (RR)-amine 84 as its
`hydrochloride in 37% yield with an enantiomeric purity
`of >99% as determined by GLC.13 Since the amine was
`too hindered to react with phenacyl halides, it was hy-
`drogenolyzed over palladium on carbon at 50 psi to give
`the primary (R)-amine 86. This amine has been prepared
`previously by resolution of the (RS)-amine with (-)-
`mandelic acid,18 (+)-tartaric acid,lg and (-bdibenzoyl-
`tartaric acid,20 and its stereochemistry has been assigned
`by deg~adativelal~ and ORD19J0 procedures. In view of the
`fact that the Czech19 and Dutchl8 workers arrived at op-
`posite conclusions, we confirmed that the levorotatory
`isomer (-1-86 had the R configuration by X-ray crystal-
`lography of the hydrochloride of the corresponding N-
`benzylamine 87.21
`Reductive alkylation of the (R)-amine 86 with benz-
`aldehyde and hydrogen over a platinum catalyst gave the
`
`(17) D. E. Nichols, C. F. Barfinecht, D. B. Rusterholz, F. Bening-
`ton, and R. D. Morin, J. Med. Chem., 16, 480 (1973).
`(18) J. van Dijk, V. G. Keizer, and H. D. Moed, Red. Trau. Chim.
`Pays-Bas, 82, 189 (1963).
`(19) 0. Cervinka, E. Kroupova, and 0. Belovsky, ColEect. Czech.
`Chem. Commun., 33, 3551 (1968).
`(20) V. P. Potapov, V. M. Dem’yanovich, and A. P. Terent’ev, Zh.
`Obshch. Khim., 35, 1538 (1965).
`(21) P. Murray-Rust, “Molecular Structure and Biological Activity”,
`W. L. Duaz, Ed., Elsevier, Amsterdam, in press.
`
`Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6 673
`N-benzyl derivative 87, which was converted into a 1:l
`mixture of the SR + RR diastereomers 89 and 90 by me-
`thod D. Although these compounds could be separated
`by fractional crystallization, a more efficient procedure
`utilized high-pressure liquid chromatography of their
`0,N-dibenzyl derivatives using a Waters Associates Prep.
`LC-system 500. Each isomer was isolated in approximately
`35% yield, and debenzylation gave the (RR)- and (SR)-
`amines 89 and 90 in greater than 99% enantiomeric purity.
`The absolute configuration of the hydrochloride of the RR
`enantiomer was established by X-ray crystallography.21
`Starting with the commercially available (S)-(+)-a-
`methylbenzylamine, we obtained the SS and RS enan-
`tiomers, 92 and 91, in a similar manner.
`
`91, RS
`92, SS
`Biological Test P r o c e d ~ r e s . ~ + ~ ~ Adrenoceptor
`blocking activities were determined in the anesthetized
`dog. The P-adrenoceptor blocking activity was assessed
`by the ability of the drug to antagonize the effects of in-
`travenously administered (-)-isoproterenol on heart rate
`and blood pressure. Antagonism of the pressor response
`to phenylephrine was used as a measure of a-blocking
`activity. The results were analyzed in the form of a Schild
`and in each instance the dose required to cause a
`10-fold displacement of the agonist dose-response curve,
`the DRlo value, was calculated. These data are expressed
`in Table IV as equipotent doses relative to propranolol
`@-blockade) and phentolamine (a-blockade), respectively.
`If required, the absolute DRlo values can be derived from
`these results using DRlo values shown for the reference
`compounds in Table VII.
`In general only one determination was made for each
`antagonist. Labetalol (34), however, has been more ex-
`Its a- and p-antagonist poten-
`tensively i n v e ~ t i g a t e d . ~ ~ ~ ~ ~
`cies, determined as above, are expressed as DRlo values
`in Table VI1 and, from experiments in vitro, as pA2 values
`in Table VIII.
`Structure-Activity Relationships. Arylethanol-
`amines having alkyl groups on the basic nitrogen, com-
`pounds 21-27, were 0-adrenoceptor blocking agents, the
`most active of which, 22, had an activity one-quarter that
`of propran~lol.~~ Substitution on the amidic nitrogen
`generally afforded less active compounds, 23-27. The
`4-isomer, 74, had a P-blocking activity one-tenth that of
`propranolol and five times that of its 5-isomer, 21.
`Some analogues when substituted on the basic nitrogen
`by specific aralkyl groups showed good a-blocking activity
`in addition to P-blockade, and compounds having this
`combination of effects, e.g., 34,46,47, and 48, caused rapid
`and sustained lowering of blood pressure in DOCA hy-
`pertensive rats and in conscious normotensive and renal
`hypertensive dogsa4 An apparently satisfactory balance
`between 0- and a-adrenergic blockade was shown by la-
`betalol(34), which was 4-16 times more potent at p- than
`at a-receptor~.~ In these compounds, the capacity to block
`a-adrenoceptors appears to be associated with the aral-
`
`(22) (a) J. B. Farmer, I. Kennedy, G. P. Levy, and R. J. Marshall,
`Br. J. Pharmacol., 45, 660 (1972). (b) I. Kennedy and G. P.
`Levy, ibid., 53, 585 (1975).
`(23) 0. Arunlakshana and H. 0. Schild, Br. J. Pharmacal., 14,48
`(1959).
`(24) C. H. Blackburn, L. J. Byrne, V. A. Cullum, J. B. Farmer, and
`G. P. Levy, J. Pharm. Pharmacol., 21, 488 (1969).
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1036-4
`IPR2016-00379
`
`

`
`Clifton et al.
`
`.-
`
`e
`
`c
`
`k
`
`a E
`
`674 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6
`
`.-
`--
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`h . .
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`n
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`h 0 .-
`c) E
`8
`2.
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`W
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`A A A ri
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`" cc
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`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1036-5
`IPR2016-00379
`
`

`
`Arylethanolamines Derived from Salicylamide
`
`z m l n
`+
`
`w
`
`t - c u m
`
`mot
`4 4 4 4 4 w z z d 4 & 4 4 4 m r 1 7
`z z z z z
`z z z z z
`
`Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6 675
`kylamine portion of the molecule, and for optimum a +
`0 blocking activity, this moiety requires (a) a three-atom
`separation of aryl from nitrogen, since compounds with a
`two-carbon and four-carbon chain, 28 and 70, respectively,
`were less active than their corresponding analogues with
`a three-carbon chain, 34, but retained some a-adrenoceptor
`blocking activity, and (b) a 1-methyl substituent, since its
`replacement by hydrogen or ethyl led to less active com-
`pounds, 33 and 59, respectively. The gem-dimethyl ana-
`logue 35 was a good 0-antagonist, but it was much less
`active at a-adrenoceptors.
`Substitution in the aromatic ring was generally disad-
`vantageous, but the profile of activity of the fluoro de-
`rivatives, 46-48, was similar to that of the unsubstituted
`compound 34 with a less favorable ratio of 0 to a potency
`in 47. Replacement of the CH2 group situated adjacent
`to the aryl group by 0, NH, or N-alkyl afforded less active
`compounds, e.g., 62, 39, and 40. Effects of alteration of
`structure on a-adrenoceptor blocking activity were un-
`predictable. Several compounds, e.g., 40,61, and 72, had
`an apparently higher ratio of a to @ blockade but only at
`the expense of the latter.
`The biological activities of the individual enantiomers
`of labetalol are shown in Table VI. From these results it
`may be seen that the @-adrenoceptor blocking activity is
`almost entirely due to the RR enantiomer. In particular,
`the R configuration for the chiral center bearing the hy-
`droxyl group is consistent with that of other aryl-
`ethanolamines known to act at P-adreno~eptors.~~ On the
`other hand, the a-blocking activity is mainly due to the
`SR isomer and, to a lesser extent, to the SS isomer. This
`observation is difficult to interpret, since labetalol repre-
`sents the first arylethanolamine with potent a-blocking
`activity. However, if this antagonism is mediated by direct
`interaction with the a-receptor and not via an allosteric
`site, then it appears that the a-receptor will accommodate
`arylethanolamines with the chiral center bearing the hy-
`droxyl group having either an R (as in epinephrineZ5g) or
`S configuration.
`a-Blockers, such as phentolamine (Regitine) or thym-
`oxamine (Opilon), are known to lower blood pressure by
`inhibiting the stimulant effects of norepinephrine at vas-
`cular a-adrenoceptors. As a consequence, they dilate pe-
`ripheral arterioles and cause a decrease in total peripheral
`resistance. This action is effective in lowering blood
`pressure in hypertensive patients but, in addition, it can
`cause postural hypotension plus an unpleasant and often
`unacceptable reflex tachycardia resulting from physio-
`logical efforts to maintain blood pressure.26 Therefore,
`nonselective a-blockers are seldom used on their own to
`treat hypertension. Conversely, the antihypertensive effect
`caused by @-blockers, such as propranolol (Inderal), is
`accompanied by a reduction in cardiac output. This
`mechanism would not be expected to cause rapid falls in
`blood pressure because the decrease in cardiac output is
`offset by an increase in peripheral resistance.26 Conse-
`quently, the simultaneous administration of drugs that
`block both a- and @-receptors would be expected to have
`an additive effect in lowering blood pressure while mini-
`
`(25) (a) J. P. Beale and N. C. Stephenson, J. Pharm. Pharmacol.,
`24, 277 (1972). (b) D. Hartley and D. Middlemiss, J. Med.
`Chem., 14, 895 (1971). (c) A. M. Anderson, Acta Chem.
`Scand., Ser. B, 29, 239 (1975). (d) A. M. Anderson, ibid., 29,
`891 (1975). (e) L. Almirante and W. Murmann, J. Med.
`Chem., 9, 650 (1966). (f) R. Howe and B. S. Rao, J. Med.
`Chem., 11,1118 (1968). (g) P. Pratesi, A. La Manna, A. Cam-
`piglio, and V. Ghislandi, J. Chem. Soc., 2069 (1958).
`(26) E. D. Frohlich, Arch. Intern. Med., 133, 1033 (1974).
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1036-6
`IPR2016-00379
`
`

`
`676 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6
`
`Clifton et al.
`
`Table V. Ketones
`
`no.
`76
`77
`78
`79
`80
`81
`82
`
`formula
`structure
`ClOH,, FO
`4-FC6H,( CH,),COMe
`CizHisNOa
`4-AcNHC6H,( CH,),COMe
`4-FC6H,0CH, COMe
`C,H,F02 C
`ClOH1,FNO
`4-FC6H,NMeCH,COMe
`Cll Hl ,NO
`4-MeC6H,NMeCH, COMe
`PhCONH-( 4-c-C,H,N)-CH2COMe C,,Ha,N20, e
`C,,H,,NO-HCl
`
`8-cH2coMe
`
`methoda yield, %
`G
`76
`100
`G
`H
`d
`H
`69
`H
`80d
`H
`60
`30 *
`H
`
`Al
`
`crystn
`solvent mp or bp (mm), "C
`79 (1.25)
`130-1 3 2
`oil
`88-92 (0.2)
`95 (0.05)
`117-120
`11 8-1 20
`
`Ea
`
`a See text. * See footnote b to Table I. Anal. C: calcd, 64.3; found, 63.8,
`e Anal. C: calcd, 69.2; found, 68.6.
`
`Purified via complex with NaHSO,.
`
`Table VI. Adrenoceptor Blocking Properties of Labetalol and Its Enantiomeric Components2*
`blockade of vascular blockade of CY ,-vascular
`blockade of cardiac
`p z receptors a
`p1 receptors a
`compd
`receptors b
`labetalol (34)
`8
`7.8
`2.4
`1.1
`RR isomer (90)
`3.7
`50.9
`SS isomer (92)
`70.4
`19.8
`309
`R S isomer (91)
`15.9
`86
`34.4
`SR isomer (89)
`56.8
`377
`4.5
`RR + S R isomers
`1.2
`6.9
`5.8
`Phentolamine = 1. See footnotes b and c to Table IV.
`a Propanol01 = 1.
`in the Anesthetized Doga* *
`Table VII.
`Relative Adrenoceptor-Blocking Actions of Labetalol, Phentolamine, and Propranolol
`
`wblockade: DR,,, mg/kg,
`for antagonism of
`PE-induced vasopressor
`responses
`8.4
`(6.7-10.4)
`1.2
`(0.9-1.6)
`>3.0
`
`p-blockade: DR,,, mg/kg,
`for antagonism of IP-induced
`positive chronotropy
`vasodepression
`(p, response)
`( p , response)
`0.53
`0.53
`(0.4-0.6)
`(0.4-0.8)
`.10.0
`>10.0
`
`0.03
`0.13
`(0.02-0.04)
`(0.09-0.17)
`95% confidence limits are given in parentheses. C IP = isoproterenol; PE = phenylephrine.
`
`drug
`la betalol
`
`phentolamine
`
`propranolol
`
`a Reference 4.
`
`mizing the side effech of either drug given independently.
`Although this therapeutically beneficial procedure has
`been established by Majid et
`using a combination of
`phentolamine and oxprenolol, it has the disadvantage that
`the absorption, pharmacokinetics, and metabolism of each
`drug are different and this may lead to problems in pro-
`viding a balanced control of blood pressure. This is less
`likely to be the case with labetalol(34), where the biological
`activity is mainly due to the independent actions of two
`structurally related compounds, the RR and SR diaste-
`reomers.28
`More recently, pharmacological studies have shown that
`
`labetalol is selective in blocking c~,-adrenoceptors**~@ (see
`Table IX) and that it possesses additional vasodilating
`actions that may contribute to the overall antihypertensive
`effect of the d r ~ g . ~ ~ i ~ ~
`
`(27) P. A. Maiid, M. K. Meeran, M. E. Benaim, B. Sharma, and S.
`H. Taylor, Er. Heart J., 36, 588 (1974).
`R. T. Brittain, G. M. Drew, and G. P. Levy, Br. J. Pharrnacol.,
`73, 282P (1981).
`G. M. Drew, Br. J. Pharrnacol., 64, 293 (1978).
`A. G. H. Blakeley and R. J. Summers, Br. J. Pharrnacol., 59,
`643 (1977).
`R. C. Dage and C. P. Hsieh, Br. J. Pharrnacol., 70,287 (1980).
`T. Baum, R. W. Watkins, E. J. Sybertz, S. Vemulapalli, K. K.
`Pula, E. Eynon, S. Nelson, G. V. Vliet, J. Glennon, and R. M.
`Moran, J. Pharrnacol. Exp. Ther., 218, 444 (1981).
`
`Human pharmacology has confirmed the a- and /3-
`adrenoceptor blocking activities of labetal01,~~ and clinical
`experience has shown it to be efficacious in reducing high
`blood pressure with minimal side effects.34 In practice,
`postural hypotension has rarely been observed when the
`drug is administered at recommended doses.6*34,35
`Experimental Section
`Melting points were determined in open capillary tubes on a
`Townson-Mercer apparatus and have not been corrected. Com-
`pounds gave satisfactory UV, IR, and NMR spectral data and
`were obtained, respectively, on Perkin-Elmer Model 137 and 402
`UV spectrophotometers, Unicam SP 100 and Perkin-Elmer 357
`IR spectrophotometers, and Varian Associates A-60A and Per-
`kin-Elmer R12B spectrometers. Microanalyses were determined
`on a F & M 185 CHN analyzer and by Dr. A. Bernhardt, 5251
`Elbach iiber Engelskirchen, West Germany. Where analyses are
`indicated only by the symbols of the elements, analytical values
`obtained were within &0.4% of the calculated values. Unless
`stated otherwise, C, H, and N analyses of compounds in the Tables
`were all within 10.4% of the calculated values. Optical rotations
`were determined on the AA-10 automatic polarimeter in methanol
`
`(33) G. Koch, Br. Heart J., 41, 192 (1979).
`(34) B. N. Prichard and D. A. Richards, Br. J. Clin. Pharrnacol.,
`8(suppl. 2), 2938 (1979).
`(35) F. D. Thompson, A. M. Joekes, and M. M. Hussein, Br. J. Clin.
`Pharrnacol., 8, 129s (1978).
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1036-7
`IPR2016-00379
`
`

`
`Arylethanolamines Derived from Salicylamide
`
`Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6 677
`
`d
`
`0
`
`3
`
`2
`
`Y
`a,
`Y
`
`N 2
`
`&
`0
`3
`v)
`
`Y 0 E
`
`4 2 0 0
`
`$
`
`V
`
`2
`
`Q
`
`3
`
`2
`
`Y v)
`I - E
`0 DII
`
`E
`0 .e
`
`4 2
`
`$+ c a
`
`Table IX. Relative Blocking Actions of Labetalol, a
`Phentolamine, Thymoxamine, and Piperoxan
`at 01 1- and OL ,-Adrenoceptors b
`
`&-antagonist activity
`(PA, values)
`postsynaptic presynaptic
`adreno-
`adreno-
`ceptors, cy1
`ceptors, a 2
`(rat, rabbit
`(guinea
`drug
`aorta)
`pig ileum)
`labetalol
`7.0-7.5
`<5.0
`phentolamine
`7.5-8.5
`8.5
`th ymoxamine
`7.0-7.5
`4.5
`piperoxan
`6.5-7.0
`7.6
`a Selectivity of other analogues was not determined.
`Reference 4.
`
`at 22 "C unless stated otherwise.
`The isomeric purity of labetalol (34) and its isomers were
`determined by GLC.lS The isomeric purity of their 0,N-dibenzyl
`derivatives were determined by HPLC on Partisil 10 using a 20
`X 0.5 cm column and eluting with hexane-ethyl acetateammonia
`(SG 0.880) (55450.1) at 250 psi; detection was by UV at 280 nm.
`Each general method discussed in the theoretical part of this
`paper is described here by only one representative example.
`Hydrogenations were carried out at room temperature and at-
`mospheric pressure unless stated otherwise.
`Methyl 2-Hydroxy-5-[ 1-hydroxy-2-[ (3-oxo-3-phenyl-
`propyl)amino]ethyl]benzoate Hydrochloride (8) (See Table
`I). A suspension of methyl 5424 (2-amino-1-hydroxyethy1)-
`amino]ethyl]-2-hydroxybenzoate hydrochloride1 (2.47 g, 0.01 mol)
`in EtOH (70 mL), PhCOMe (4.8 g, 0.04 mol), and paraform-
`aldehyde (0.7 g) was stirred under reflux for 6 h. Solvent was
`removed under reduced pressure, and the residue was triturated
`with EtzO (200 mL) and recrystallized.
`Preparation of Salicylamides (See Tables 11-IV). Method
`A. 2-Hydroxy-4- [ 1- hydroxy-2-[ N - ( 1-met hylet hy1)-N- (phe-
`nylmethyl)amino]ethyl]benzamide (19). A solution of methyl
`2-hydroxy-4-[ 1-hydroxy-2- [N-( 1-me