J.Med. Chem. 1982,25, 352-358
352
Dopaminergic Activity of Substituted 6-Chloro-1-pheny l-2,3,4,5- tet rahydro-1H-3-bemaze pines Francis R. Pfeiffer,*J James W. Wilson,? Joseph Weinstock,? George Y. Kuo,? Pamela A. Chambers,? Kenneth G. Holden,? Richard A. Hahn,*J*Joseph R. Wardell, Jr.,* Alfonso J. Tobia,*Jb Paulette E. Setler,*Jc and Henry M. Saraut Research Chemistry and Biological Research, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101, Received August 27, 1981
6-Chloro-7,8dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were synthesized and evaluated as agonists of central and peripheral dopamine receptors. These benzazepines were prepared by cyclization of certain amino alcohols followed by demethylation of the 7,8-dimethoxy groups of the precursors to the 78-catecholicmoiety. Preliminary evidence of dopaminergic activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanyingchanges in renal vascular resistance. The most potent compounds contained an hydroxyl group on the 1-phenyl group or were substituted at the 3' position with a chloro, methyl, or trifluoromethyl group. Evidence for central dopaminergic activity was obtained by measuring rotational effects in rata lesioned in the substantia nigra and also in an in vitro assay which measured stimulation of rat striatal adenylate cyclase. The compounds with the best central dopaminergic activity were generally the benzazepines which were the most lipophilic, were substituted on the 3' position of the 1-phenylgroup, and contained either a 3-N-methyl or 3-N-alla group. Dopaminergic receptors have been identified in the central nervous system and in the Recent reports from our laboratories4 have described the profiles of dopamine agonistsgl1 and antagonists.12 The central and peripheral dopaminergic activities of 1, 7,8-di-
Scheme I
T HO
"'GR F'
C'
HO
Y
1 (SK&F 38393), X = Y = H 2 (SK&F 82526), X = C1; Y = OH 3, X = H; Y = OH
hydroxy-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 38393), were reported:^^ and the selective peripheral dopamine agonist activity of 2, 6-chloro-7,8-dihydroxy-1- (4-hydroxypheny1)-2,3,4,5-tetrahydro-lH-3benzazepine (SK&F 82526), was demonstrated.'l In contrast to the substantial renal vasodilator activity exhibited by 2, the 6-dechloro derivative 3 was inactive as a renal vasodilator.ll This paper describes the SAR of other 6chloro derivatives of 2 with chemical modifications on the 3-benzazepine nucleus aimed at functionalization of the 3-nitrogen and substitution on the 1-phenyl ring. On the basis of the earlier studies reported with compounds in this series, we have interpreted increases in renal blood flow (dog) as evidence for the activation of renal dopamine receptors. Similarly, we have interpreted contralateral rotational effects in rats with a unilateral lesion in the substantia nigra and activation of dopamine-sensitive rat striatal adenylate cyclase (in vitro) as evidence for centrally mediated dopaminergic activity. Chemistry. The synthesis of the 3-benzazepines is shown in Scheme 1. The requisite aldehydes 4 were converted t o the oxiranes 5 via dimethylsulfonium methylide,13 and the crude oxiranes 5 were heated a t 110 OC with 2-chlorohomoveratrylamine (6)" to produce the amino alcohols 7 (see Table IV). Compounds 7 were usually purified by direct crystallization of the reaction mixture 'Research Chemistry. Biological Research.
CH3O
*HBr
Q X
Q X
8
QX
9
or, when necessary, by column chromatography, since it was beneficial to use clean 7 for cyclization to the 3(1) (a) Present address: Lilly Research Laboratories,Indianapolis IN. (b) Present address: Ortho Pharmaceutical Corp., Raritan NJ. (c) Present address: McNeil Laboratories, Fort Washington, PA. (2) L. I. Goldberg, Pharmacol. Rev., 24, 1 (1972). (3) (a) L. L. Iverson, Science, 188, 1084 (1975);(b) J. G.Cannon, Adv. Biosci., 20, 87 (1978). (4) P. E. Setler, R. G. Pendleton, and E. Findlay, J . Pharrnacol. E z p . Ther., 192, 702 (1975). (5) J. W. Kebabian and D. B. Calne, Nature (London), 277, 93 (1979).
0022-2623/82/1825-0352$01.25/00 1982 American Chemical Society
Substituted 1H-3-Benzazepines
Journal of Medicinal Chemistry, 1982, Vol. 25, No. 4 353
derivatives 1Oq and 10s (see Table I). Structure-Activity Relationships. The biological activities of the benzazepines are summarized in Tables I and 111. Effects on systemic blood pressure (MABP), heart rate (HR), and renal blood flow (RBF) were measured in anesthetized dogs by techniques previously de12 scribed.%l’ Renal vasodilator activity was first determined CI CI qualitatively. The renal vascular resistance (RVR) was calculated as the ratio of the MABP to mean RBF. Other 48% HBr details of this protocol can be found in Table I. The most active compounds from the primary renal vasodilator screen were then subjected to a secondary analysis, and these results are listed in Table 111. Cumulative doseresponse data were obtained by infusing the drug at progressively increasing infusion rates, and each dose level was 13, R = H 111, R = H infused for 5 min. The potency for each compound is 14, R = CH, m, R = CH, expressed as the average minimum cumulative dose which decreased RVR by 15% The maximum renal vasodilator effect is expressed as the average maximum percent deScheme I11 crease in RVR attainable with the compound. The seCl CI lectivity ratios are the separations between the RVR EDl5 and doses producing a 30% change in iliac vascular resistance (IVR),a 20% change in W P , and a 20% change in HR. Drug effects on central dopaminergic activity were determined by procedures and parameters described previously,* and the test results are listed in Table I. It can be seen in Table I that loa, the prototype for this series of compounds, has both central and peripheral acl o p , R = p-OCH,-C,H, 1Oa tivity. Compound 10a is equipotent to dopamine as a renal r, R = p-CF,-C,H, vasodilator and is more active than dopamine in its central effects.” The 7,8-diacetoxy derivative 10b was equipotent to 10a as a renal vasodilator, suggesting that 7,a-diesters benzazepines. When compounds 7 were heated at 115 “C are prodrug equivalents of the catecholic moiety. The with 48% HBr, the 7,8-dihydroxy-3-benzazepines 10 and 3-N-methylbenzazepines lOc,d,w and 1lh,m were essen11, which are listed in Table I, were isolated directly as tially inactive in the primary renal vasodilator screen, inthe HBr salts. Cyclization of 7 with H2S04in CF3COOH dicating that secondary amines are usually required for a t 25 “C gave the 7,8-dimethoxy-3-benzazepines 8 shown optimal activity. The exceptions are the allyl derivatives in Table 11, which were then alkylated or acylated on nilOj, lox, l l j , and the 2-furanylmethyl derivative 10m. trogen prior to cleavage of the methyl ethers with BBr3 Other N-alkyl derivatives 10e-h were marginally active in in CH2C12. The rn-trifluoromethyl derivatives 111 and 1l m reducing renal vascular resistance. The 3-N-2-thienylwere prepared by an alternative procedure as shown in methyl analogue 10n, in contrast to 10m, was significantly Scheme 11. 2- [3-(Trifluoromethyl)phenyl]-2-methoxyethyl but marginally active a t the highest test dose. Functionbromide (f2)l4was heated with 6 and K2C03to give 13, alization on nitrogen with the relatively large benzyl group which was converted to 14. Subsequent treatment of 13 and 14 with hot HBr gave 6-chloro-7,8-dihydro-l-[3-(tri- para substituted with a methoxyl(1Oq) or a trifluoromethyl fluoromethyl)phenyl]-2,3,4,5-tetrahydro-lH-3-benzazepine (10s) was not particularly beneficial. All of the above benzazepines contained an unsubstihydrobromides 111 and l l m . Scheme I11 portrays the tuted l-phenyl group. Variations on the l-phenyl group preparation of the amides lop and 10r from 10a and the have provided compounds with exceptional activity. The reduction of these amides with diborane t o the benzyl 4’-hydroxy analogue (2) of 10a exhibited outstanding activity as a renal vasodi1ator;ll the 3’-hydroxy isomer 10t showed good activity but of lowered magnitude relative I. Creese and S. H. Snyder, Eur. J. Pharmacol., 50,459 (1978). I. Creese, D. R. Burt, and S. H. Snyder, Science, 192, 481 to 2. The 4’-chloro derivative 1Ou did not significantly (1976). increase RBF; however, the 3’-chloro isomer 1Ov was very P. E.Setler, H. M. Sarau, C. L. Zirkle, and H. L. Saunders, significantly active and its 3-N-allyl derivative lox showed Eur. J. Pharmacol., 50, 419 (1978). good activity. The combination of hydroxyl and halo R.G.Pendleton, L. Samler, C. Kaiser, and P. T. Ridley, Eur. groups on the l-phenyl afforded 1Oz and lla-d, with the J. Pharmacol., 51, 19 (1978). 4’-chloro-3’-hydroxyl derivatives 1l a , b being the most R. A. Hahn and J. R. Wardell, Jr., J. Cardiovasc. Pharmacol., 2, 583 (1980). potent. The 3’,5’-dichloro-4’-hydroxyl 1IC was less active J. Weinstock, J. W. Wilson, D. L. Ladd, C. K. Brush, F. R. than lla. Substitution of a methyl group at the 2’ and 4’ Pfeiffer, G. Y. Kuo, K. G . Holden, N. C. F. Yim, R. A. Hahn, positions (1le,f) did not enhance activity, but the 3’-methyl J. R. Wardell, Jr., A. J. Tobia, P. E. Setler, H. M. Sarau, and 1lg and the corresponding N-3-allyl 11j exhibited good P. T. Ridley, J. Med. Chem., 23, 973 (1980). activity as renal vasodilators. Other 3’-functionalized C. Kaiser, F.E. Ali, W. E. Bondinell, M. Brenner, K. G. Holanalogues, including the trifluoromethyl derivative 111, den, T. W. Ku, H. Oh, S. T. Ross, N. C. F. Yim, C. L. Zirkle, R. A. Hahn, H. M. Sarau, P. E. Setler, and J. R. Wardell, Jr., were modestly active. J. Med. Chem., 23, 976 (1980). The most active renal vasodilators listed in Table I were E.J. Corey and M. Chaykovsky, J. Am. Chem. SOC., 84,3782 then studied more rigorously, and the results of these (1962). investigations are shown in Table 111. Compound 2 was M. Sahyun and N. R. Hand, Belgium Patent 648692 (1964); Chem. Abstr., 63, 13147h (1964). clearly the most potent benzazepine, and it also showed
Scheme I1
.
Pfeiffer et al.
364 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 4
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Journal of Medicinal Chemistry, 1982, Vol. 25, No, 4 355
Substituted 1H-3-Benzazepines
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356 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 4
Pfeiffer et al.
Table 11. 6-Chloro-7,8-dimethoxy-3-benzazepines (8 and 9)
cH30G \
R 'HX
CH3O
4'
compd 8a
H H
9e
H H H H H
c1 c1 CH, CH, CH,
H CH, H CH, CH,CH=CH, H CH, CH,CH=CH,
9f
H
CH,
CH2-Q
9a
8b 9b 9c
8c
9d
c1
X
mp, "C
recrystn solventa
c1 c1 c1 fumarate C1 C1
243-244 233-234 160-163 197-199 192-194 132-140 185-187 178-180
A B C D C E E F
c1
235-237
B
R
3'
4' H H H
c1
fumarate
formula C,,H,,ClNO,~HCl C,,H,,ClNO,.HCl C,,H,,C1,NO;HCIC
ana1.b
C,,H,,ClNO,*HCI
C, H, N C, H, N C, H, N C, H, N C, H, N c , H, N C, H, N C, H, N
C,H,,CINO,*HCld
C, H, N
Cl,H,lC1,N0,~C4H,0,
C,,H,,Cl,NO,*HCl C,,H,,ClNO,*HCl C~oH,ClN0,~C4H404
9g C1 OCH, CH,CH=CH, C1 163-165 D C,,H,,Cl,NO,*HCl C, H, N Recrystallization solvents: A, 2-propanol-ether;B, MeOH-ether; C, acetone-ether; D, EtOH; E, acetone; F, EtOAc. Analytical results in this table were within k0.4 of the theoretical values. Calculated for 0.5 mol of H,O. d Calculated for 0.25 mol of H,O. (1
Table 111. Renal Vasodilator Activitya RVR d k g iv 3.5 (2) 45 (2) 4.5 (3) 200 (2) 0.3 (5) 0.35 (2) 22 (2) 99 (3) 61 (3) 19 (3) 165 (4) 2 (2) 15 (3) 8 (2) 2.7 (3)
av max
IVR ED,/ RVR ED,, 628 0.1 929 >6072 >6072 34 >6072 -1 > 249
MABP ED,,/ HR ED,,/ RVR ED,, RVR ED,, 39 >1734 108 16 18 >6072 1Oe 1Of 42 >6072 > 6072 1Om 26 >6072 > 6072 2 59 >6072 >6072 lot 49 >6072 1029 38 > 6072 >6072 1ox 56 -3 0 102 > 249 > 249 25 lla llb 39 >319 >319 llc 18 > 37 > 37 > 37 26 15 > 2995 > 2995 1 Id 1 56 >6072 7 Ilg 44 10 > 6072 75 111 dopamine 36 56 113 141 a See ref 11 for details of methodology for determining RVR ED,,, average maximum percent decrease in RVR, and the selectivity ratios ED,, relative to iliac vascular resistance (IVR), mean arterial blood pressure (MABP),and heart rate (HR). The following changes were determined to be the minimum necessary for statistical significance = 0.95): RVR, 16%; MABP, *6%; IVR, +24%;HR, +9%. Number of dogs used in test are in parentheses. compd 1Oa
% J . RVR
excellent selectivity for the renal vasculature. The 3'hydroxy analogue 10t was nearly as potent as 2 but was not as selective. Compound 10s exhibited excellent selectivity ratios, but was 70 times less potent than 2. Compound 10a was one-tenth as potent as 2 and was not selective for the renal vasculature. In summary, the renal vasodilator data show that of the 6-chlorobenzazepines, (1)the hydroxy-substituted 1-phenyl derivatives are the most active, (2) the 3' position of the 1-phenyl group substituted with hydroxyl, chloro, methyl, or trifluoromethyl provided active compounds, (3) the 3-N-allyl group imparts activity in those derivatives in which the corresponding 3-N-methyl derivatives were inactive, and (4) the 3-benzazepines not derivatized on nitrogen were the most potent compounds. The relationships between structure and central dopaminergic activities are found in Table I. The compounds were routinely tested for contralateral rotation in lesioned rats by intraperitoneal (ip) administration. Oral activity (po) was a primary goal for a central dopaminergic agonist,
and the more active compounds were studied for this potential use. Intrinsic activity was measured by intracaudal (ic) administration. Compound 10a has potent central dopaminergic activity as can be seen in the ip, PO, and ic rotation test results and by the high activity as a stimulant of rat striatal adenylate cyclase. The N-methyl ( ~ O C ) , N-ethyl (lOe),and N-allyl (lOj)derivatives of 10a exhibited good activity in the rat rotation and cyclase tests, but the 7,8-diacetoxy (101) derivative of lOj was orally inactive a t 10 mg/kg. Compound 10n was one-half as potent as 10a in the rat rotation test. The 4'- and 3'-hydroxy analogues (2 and lot) were inactive by ip administration, but by the ic route 2 was shown to have good intrinsic activity. Compounds with the 1-phenyl group substituted with a chloro (1Ou-x) were about one-tenth as active as loa, and 10s was the most active. Compound lox also was a good stimulator of rat striatal adenylate cyclase. The 3'-methyl analogues llg, 11h, and 11j were clearly potent in the rat rotation tests, and compound l l j was the most active. Compound 111 was active when administered ip but was
Substituted 1H-3Benzazepines
Journal of Medicinal Chemistry, 1982, Vol. 25, No. 4 357
Table IV. Amino Alcohol Precursors of 3-Benzazepines (7) CI
5' 6
0:; \
4'
compd 4' 3' 2' mp, "C recrystn solvent yield,a % 7a H OCH, 96-97 H acetone-ether 7 7b C1 H H 99-100 EtOH 10.5 c1 H 164-165 7c H EtOH 21 7d OCH, C1 H 115-117 EtOH 9 7e C1 OCH, H 123-125 EtOH 17 7f OCH, C1 5'421 116-118 EtOH 10 H 7g OCH, Br 131-133 MeOH 17 7h CH, H H 117-118 EtOH 12 98-99 EtOH 10 CH, H 7i H EtOH CH, 116-118 7j H 11 H 7k CF, H H 109-110 EtOH 12 Yields were calculated from the substituted benzaldehydes. inactive when given orally. All of the other compounds were less potent or inactive. In summarizing the central dopaminergic actions of these benzazepines, it can be seen that (1)the most lipophilic compounds exhibit the best activity in the rat rotation testa, (2) the 3' position on the 1-phenyl group when substituted with chloro, methyl, or trifluoromethyl provide compounds with enhanced activity when compared to the 2' and 4' analogues, and (3) the N-methyl and N-allyl derivatives impart good central dopaminergic activity to these benzazepines.
Experimental Section Column chromatography was carried out on Merck silica gel 60 (MC/B, Cincinnati, OH). Proton magnetic spectra were run on Varian T-60 and Varian EM-360 (60 MHz) instruments using MeSi as reference. Infrared spectra were run on a Perkin-Elmer Infracord Model 137. Melting points were taken on a ThomasHoover melting point apparatus and are uncorrected. TLC's were run on Uniplate precoated silica gel plates, 250 Km (Analtech, Inc., Newark, DE). Solvents were dried over MgSO,. m-Anisaldehyde, m- and p-chlorobenzaldehydes, and 0-,m-,and ptolualdehydeswere commercialsamples which were not purified. 3-Chloro-4-methoxybenzaldehyde and 3,5-dichloro-4-methoxybenzaldehyde were prepared as described.16 4-Chloro-3-methoxybenzaldehyde was synthesizedfrom 4-chloro-3-methoxybenzoic acidIs by reduction with BzH6to the benzyl alcohol, followed by oxidation with activated MnOz at 80 OC in toluene. 3-Bromo4methoxybenzaldehyde" was also prepared by a redox procedure. 4-(Trifluoromethyl)benzaldehyde was obtained by hydrolysis of the oxime18at 25 OC with 3 N HCl in MeCN in the presence of excess CH3CH0. All compounds were routinely checked by IR, NMR,TLC, and mass spectrmcopy. Where analyses are indicated only by symbols of the elements, results obtained were within *0.4% of the theoretical values. 3-Brom0-4-methoxy-a-[[N-(2-chloro-3,4-dimethoxyphenethyl)amino]methyl]bnzyl Alcohol (7g). A suspension of 14 g (0.28 mol) of 50% NaH in mineral oil in 300 mL of MezSOwas heated at 65-70 OC for about 80 min to give a nearly clear, greenish solution. Then 150 mL of dry THF was added, and the mixture was cooled in ice-HzO. A solution of 57.2 g (0.28 mol) of trimethylsulfonium iodide1*in 400 mL of Me,SO was added over ~
~~
~
(15) D.Ginsburg, J. Am. Chem. SOC.,73,702 (1951). (16) R. Grice and I. W. Owen, J. Chem. SOC.,1951 (1963). (17) G. W. Gray, B. Jones, and F. Marson, J. Chem. SOC.,1417 (1956). (18) C. F. Barfknecht and T. R. Westby, J. Med. Chem., 10,1192 (1967).
formula C19H24C1N04
C,,H,,CI,NO, C18H21C12N03
C19H23C12N04 C19H23C12N04 C19H22C13N04
Cl9H2,BrC1NO, C,,H,ClNO, C,,H,ClNO, C19H24C1N03
C,,H2,ClF,N03
anal. C, H, N C, H, N C, H, N C, H, N c, H, N C, H, N C, H, N, Br C, H, N c, H, N C, H, N C, H, N
10 min. After the mixture was stirred for an additional 5 min, a solution of 40 g (0.186 mol) of 3-bromo-4-methoxybenzaldehyde in 150 mL of THF was added over 10 min. The mixture was stirred at 0 OC for 15 min and then at 25 "C for 2 h, diluted with 4 L of ice-HzO, and extracted several times with EtOAc, and the extracts were washed with brine. The dried crude oxirane 5 (38 g) (TLC with cyclohexane/EtOAc, 32, showed one major material with an R, of 0.48) was mixed with 30 g (0.14 mol) of 242chloro-3,4-dimethoxyhenyl)ethylamine(6)l' and heated at 110 OC for 18h under NP The cooled reaction mixture was triturated with EtOAc to give a voluminous solid, which was collected and washed with 1:l EtOAc-petroleum ether to afford 20.5 g (17%) of 7g. An analytical sample was prepared from EtOH. Table IV lists other amino alcohols (7) which were prepared using the same conditions. When crystallization could not be induced directly, purification was achieved by column chromatography on silica gel with a 0.5 to 2% of MeOH in CHzClzgradient. 6-Chloro-7,8-dimethoxy-l-(3-chlorophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (8b). In 50 mL of CF3COOH was dissolved 7.5 g (0.02 mol) of 7c, and then 2.5 mL of HzS04was added. The solution was refluxed for 2 h, concentrated in vacuo, basified with cold NaOH solution, and extracted with EtOAc. After the solution was washed with HzO, the dried, concentrated product (7.5 g) (TLC with EtOAc/MeOH/NH,OH, 75:23:2, showed one spot with an Rf of 0.55) was converted to the hydrochloride salt with ethereal HCl to provide white powdery 8b.HBr. In Table I1 are listed other benzazepines prepared by this method, 6-Chloro-7,8-dimethoxy-3-methyl-l-(3-chlorophenyl)2,3,4,5-tetrahydro-lH-3-benzazepine(9b). A solution of 3 g (8.5 mmol) of 8b, 15 mL of 37% HCHO, and 18 mL of 88% HCOOH was heated on the steam bath for 4.5 h, diluted with ice, and basified with NaOH solution, and the product was extracted into EtOAc and washed with H20. The crude material (2.6 g) was chromatographedon 125g of silica gel with a 1to 2% of MeOH in CHzClzgradient to give 2.2 g (71%) of homogenous 9b (TLC with 4% MeOH in CHzClzshowed an Rf 0.85). A fumarate salt was prepared with ethanolic fumaric acid. In Table I1 are listed other 3-methylbenzazepines synthesized by this procedure. Other 3-alkyl-7,8-dimethoxyprecursors of compounds 10e-h listed in Table I were prepared by alkylation of 8a with the following reagents: R = Et, CzH@r (excess),KOH (4equiv), MeOH, 8 h, 135 OC (bomb) (100% yield); R = CHzCH20H, BrCHzCHzOH(1.5 equiv), KzCO3 (4 equiv), DMF, 145 OC, 8 h (88%yield); R = Pr, C3H7Br(1.5 equiv), K&O3 (4equiv), DMF, reflux, 1 h (85% yield); R = Bu, C4H9Br(1.5 equiv), K2C03(4 equiv),DMF, reflux, 1h (83% yield). The above compounds were checked by the usual parameters and were usually used without further purification for the BBr3cleavage reaction. If necessary, the 3-alkyl derivatives were passed through a silica column with
358 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 4
Pfeiffer et al.
a 1 to 4% of MeOH in CHzClzgradient. 6-Chloro-7,8-dihydroxy1-(3-hydroxypheny1)-2,3,4,53-Allyl-6-chloro-7,8-dimethoxy-l-(3-methylphenyl)- tetrahydro-1H-3-benzazepine (lot). A mixture of 1.7 g (4.7 mmol) of 7a and 2.5 mL of a 48% HBr solution was heated in 2,3,4,5-tetrahydro-lH-3-benzazepine(9e). A mixture of 3 g an oil bath held at 135 "C for 3 h under N2 The reaction was (9 mmol) of 8c,5.5 g (40 mmol) of KZCOs, and 1.2 g (10 mmol) of allyl bromide in 100 mL of dry DMF was heated at 120 "C (oil diluted with 2 volumes of H20 and evaporated to a dark foam. bath temperature) for 2 h under N2 The DMF was evaporated, This was dissolved in MeOH, treated with activated charcoal, the residue was partitioned between HzO and EtOAc, and the filtered, and concentrated to a pale yellow syrup. This was EtOAc was washed with HzO, dried, and concentrated to 2.2 g dissolved in CH&N and added to ether to give a nearly white (66%) of 9e,which was homogeneous on TLC (Rf0.88 with 5% hygroscopic solid. After the solid was dried at 65 "C (1mm), the MeOH in CHzCl2). A hydrochloride salt was prepared with white powdery hydrobromide salt of lot was obtained (1.2 g, 66%). In Table I are listed other compounds prepared by cyclizaethereal HCl. The other 3-allyl derivatives listed in Table I1 were prepared by this method. tion/demethylation of the amino alcohols 7 to the 7,8-di6-Chloro-7,8-dimethoxy-3-(2-furanylmethyl)-l-(3- hydroxy-3-benzazepines10 and 11. Other compounds prepared methylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine (9f). A by this method are lOu,v,zand lla,e-g,l. mixture of 0.7 g (2.1 mmol) of 8c,0.69 g (3.3 mmol) of the white, 1-( 3-Bromo-4-hydroxyphenyl)-6-chloro-7,8-dihydroxy2,3,4,5-tetrahydro-lH-S-benzazepine (1 la). To an ice-cold crystalline N-hydroxysuccinimideester of 2-furoic acid (prepared solution of 12.5 g (0.029 mol) of 7g in 150 mL of dry CHzClzwas with DCC in THF), 0.5 g of NaHCO,, 5 mL of HzO,and 2.0 mL of 2-methoxyethanol was stirred for 4 h at 25 "C. Brine was added, added dropwise 184 mL (0.146 mol) of BBr, in CHZCl2(from a and the product was extracted into CHZClzto give 4 g of the crude solution of 1g/5 mL). An initial greenish precipitate gradually syrupy 3-(2-furanyl) amide. This was chromatographed on 125 dissolved as the solution was being stirred at 25 "C for 18 h. The g of silica gel with a gradient of 20 to 33% of EtOAc in cyclomixture was recooled, excess MeOH was added, and the solvents were evaporated and azeotroped with MeOH to afford a tannish hexane. The homogeneous fractions (3.31 g, 86%) (R 0.45 on TLC with 3:2 cyclohexane/EtOAc) gave the expected IR and solid. This was suspended in hot MeCN, and MeOH was added NMR spectra. The amide (0.8 g, 1.9 mmol) was dissolved in 20 to complete the solution. About one-half of the solvent was mL of dry THF and cooled to -15 "C, and BH3 (6 mmol) in THF evaporated in vacuo to incipient crystallization,the mixture was (from a solution 1 M in BH,) was added dropwise. Then the chilled to -30 "C, and the beige crystals were filtered and washed mixture was stirred at 25 "C for 3 h and recooled, and excess with cold MeCN to give 9.1 g (67%) of the hydrobromide salt of lld. Other compounds prepared by BBr, demethylationare found MeOH was added cautiously. The solvents were evaporated,and in Table I and include lOc,e-j,w,x and llb,h,j. the residue was treated with ethereal HCl to give 9f (Table 11). 6-Chloro-7,8-dihydroxy-3-(2-furanylmethyl)-l-(3-methyl- 3-(Trifluoromethy1)-a-[[ (2-chloro-3,4-dimet hoxyphenphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine(1 lk). Comethyl)amino]methyl]benzyl Methyl Ether (13). A mixture pound 8c was converted to the 3-(2-furanyl)amide as described of 8.4 g (0.039 mol) of 6,11.0 g (0.039 mol) of 12," 5.6 g (0.04 mol) for 9f. A solution of 3.3 g (7.8 mmol) of this amide was dissolved of KzCO,, and 30 mL of toluene was heated at 105"C and stirred in 50 mL of dry CHzClzand cooled to -15 "C. Then 6.5 g (2.6 for 3 h. The reaction partially solidified. After cooling, the residue mmol) of BBr, (32.6 mmol of a solution of 1g of BBr, per 5 mL was partitioned between a 5% NaHCO, solution and EtOAc. The of CHZClz)was added dropwise, cooling was stopped, and the EtOAc layer was washed with brine, dried, and concentrated to about 20 g of an oil. This was chromatographed on 500 g of silica mixture was stirred at 25 "C for 1 h. Excess MeOH was added gel with 1to 2% of MeOH in CHZCl1. The homogeneous fractions cautiously at 0 "C, the solvents were evaporated, the solid (3.1 (TLC with CHzClz/MeOH,91, gave an Rfof 0.76) were dissolved g) was homogeneous on TLC (Rf0.27 with 3 2 cyclohexane/FtOAc) in ether and acidified with ethereal HCl to give a solid, which was and exhibited the proper NMR spectra, and field-desorptimmasa crystdized from MeCN to afford 5.5 g (31%)of the hydrochloride spectra gave a molecular weight of 397. The crude 7,8-dihydroxy C, H, N. salt of 13,mp 200-202 "C. Anal. (CmHZ3ClF3NO3.HC1) amide was dissolved in 40 mL of dry THF, 2.0 mmol of BH, (1 6-Chloro-7,8-dihydroxy-3-methyl-l-[3-( trifluoromethy1)M in THF) was added, and the procedure described for 9f was phenyl]-2,3,4,5-tetrahydro-lH-3-benzazepine(llm).A sofollowed. The crude Ilk was digested with 50 mL of 3 N HC1 lution of 3.6 g (8.6 mmol) of the free base 13, 20 mL of 37% at 50 "C for 30 min, evaporated in vacuo, and azeotroped with HCHO, and 26 mL of 88% HCOOH was heated on the steam bath EtOH to give the white solid hydrochlorideof Ilk (1.86 g, 51%). for 5 h, diluted with ice, basified with 10% NaOH solution, and Compound 10n (Table I) was prepared by essentially the same extracted with EtOAc. The washed and dried residual oil 14 was conditions used for Ilk,except that the solid N-hydroxysuccindissolved in 25 mL of HOAc and 50 mL of 48% HBr solution and imide ester of 2-thiophenecarboxylicacid was employed. Comheated in an oil bath held at 125 "C for 5 h under N2 The cooled pounds 1Oy and 10m were prepared by the procedure used for mixture was diluted with MeOH, treated with activated charcoal, Ilk. 6-Chloro-7,8-dihydroxy-3-(4-methoxybenzoyl)-l-phenyl- and evaporated to an amber residue. This was triturated with MeCN to provide 510 mg (13%)of the hydrobromidesalt of llm. 2,3,4,5-tetrahydro-lH-3-benzazepine (lop). A solution of 4 An analytical sample was prepared from absolute EtOH, mp g (0.011 mol) of loa, 2.6 g (0.015 mol) of 4-methoxybenzoyl 264-266 "C. chloride, 3.7 g (0.044 mol) of NaHCO,, and 100 mL of 50% 6-Chloro-7,8-diacetoxy-1-phenyl-2,3,4,5-tetrahydro-lH-3aqueous acetone was stirred overnight at 25 "C. The acetone was benzazepine (lob). To a suspension of 2.5 g (8.7 mmol) of 10a evaporated, the aqueous residue was extracted with EtOAc, and in 50 mL of CF3COOH was added 3.2 g (26 mmol) of acetyl the extracts were washed with a 5% NaHC0, solution and HzO. bromide, and the mixture was refluxed for 2 h as 10a dissolved. The crude, concentrated product was crystallized from MeOH The solvent was evaporated, and the residue was partitioned to give 3.73 g (M%)of lop. Compound 10r (TableI) was prepared between cold NaHC0, solution and ether. The ether layer was by this procedure in 63% yield. washed with NaHC03 solution and brine, and the dried con6-Chloro-7,8-dihydroxy-3-(4-methoxybenzyl)l-phenylcentrated product was acidified with ethereal HC1. The white 2,3,4,5-tetrahydro-lH-3-benzazepine (1Oq). To a solution of precipitate was recrystallized from MeOH-ether to give 1.7 g 21 mL of 1 M BH, in THF was added a solution of 2.2 g (5.2 (48%) of the hydrochloride salt of lob. Compounds 10d and 101 mmol) of lop in 110mL of dry THF. The resulting solution was were also prepared by this procedure. refluxed for 2 h, excess MeOH was added to the cooled mixture, and the solvents were evaporated. The residue was dissolved in Acknowledgment. We thank Paul Woodward, James 30 mL of MeOH and 30 mL of 6 N HC1 and refluxed gently for M. Smith, Maryann Malesky, Cynthia Smith, and Joseph 30 min. The solvents were evaporated, and the residue was McDevitt of Biological Research for expert technical asazeotroped with EtOH to provide a white solid. A crystallization sistance. We are grateful to Edith Reich and Gail Johnson from MeOH gave 1.5 g (65%) of the hydrochloride salt of 1Oq. for elemental analyses and Gerald Roberts and Dr. Susan Compound 10s was prepared by this procedure in 69% yield (see Rottschaefer for mass spectral data. Table I).
