formation of 3-nlIyl-l-substituted-B,7,S-trimethoxy-~,4dihydroisoquinolines IV-VI11 (42-46, Table 111). CH ,O CH O-@-
CHJHNHCOR CHICH=CHL I
--
CH 0 IV,R-CH, V R=CGH, VI, R = C6H CHJCH,
reiiilted in the isolation of cthyl '1-(.3,1,.i-triniethoxybenzy1)-4-pentynoate. This ester was then saponified and the acid produced was converted into XI11 via reaction with ethyl chlorocarbonate, followed by SH3. When attempts were madc t o convert XI11 into l-(3,4,.~-trimethoxybenzyl)-3-but~~nylamine by the Hofmann rearrangement using Br2 and SaOH, a pure product could not be isolated. Honever, when the CH 0,
VII. R =C,H,CH=CH VIII. R =
@ CHO
R
-
CH10-@CH2~HNHCOOCH, CH,O
LAH
CH,CH=CH,
N - Benzoyl - 2 - (3,4,5-trimethoxybenzyl)-4-pentenylamine (IX) (40, Table 11) mas cyclized similarly to form l-phenyl-4-all~l-7,S,9-trimethoxy-4,~-dihydro-3~,2-benzazepine (X). CH 0, I
/
CHZC=CH
CHjO
XV IX CH,,O
FhHi
CH $0 CH1CH=CH2
X Catalytic hydrogenation of 1-(3,4,5-trimethoxgbenzyl)-3-butenylamine (11) resulted in the formation of l-(3,4,5-trimethoxybenzyl)b ~ t y l a m i n e . ~ The synthesis of the isomeric 2-(3,4,5trimethoxypheny1)-4-pentenylamine (XII) by L,4H reduction of the nitrile XI furnished a liquid €or which good elemental analysis could not be obtained. X maleate salt of XI1 was prepared and an N-carbethoxy derivative was readily obtained.
Hofmann reaction was carried out in NeOH using XaOC1, the carbamate XIV was obtained. LAH reduction yielded N-methyl-l-(3,4,5-trimethoxybenzy1)-3butynylamine (XY). The amide I was readily converted into the nitrile XVI and reaction of XT'I with hydroxylamine produced the amidooxime XVII. CH O\
/
CH?CH=CH,
CHjO
XVI CH ,O
NOH
II
CHCH-C-YH, -1 CH,CH=CH,
CH ,O
CH 0,
XVII
CHCHJHZ
I
CH-0
CH2CH=CH2 XI1
The preparation of 2-(3,4,5-trimethoxybenzyl)-4pentynamide (XIII) was carried out by a sequence of reactions similar to that employed for the corresponding pentenamide (I).l Thus ethyl sodio-2-propargylacetoacetate was alkylated with 3,4,5-trimethoxybenzylchloride, and subsequent cleavage of the acetyl group (3) A . T. Shulgin, Experzentia, 19, 127 (1963).
Pharmacology.-Compounds were screened for oral hypotensive activity in conscious, renal hypertensive iats. Male Wistar rats were made hypertensive by a modified Grollman t e ~ h n i q u e . ~Animals with a systolic pressure greater than 150 mm were considered hypertensive. Systolic blood pressure was measured indirectly by means of a Decker tail plethysmograph system. Active compounds were those producing a mean fall in systolic pressure of 20 mm or more. Compounds were administered by gastric gavage a t their minimal symptomatic dose or a maximal dose of 250 mg/kg. Compounds 1, 2, 3, 8, 9, 27, 29, and 31 (Table I) were active in the initial screen. All other compounds in this report were inactive. Thus the only ?\' substituents which retained the activity of 1 were Me, Et, carbo(4) 4 . Grollman. P r o r . S o c . R x p . Biol. .Wed,, 57, 102 (1044).
!I
I1
1(1
11
12 1:;
14 13 16
17
ri
methoxy. carbethoxy, phenethyl, 3,4,3,trimethoxyt)enzyl, or oxazolinyl. In all cases, N,S-disubstituted compounds were devoid of hypotensive activit? . Intravenous injection of the active compounds also
r c d t e d in rrductiori of blood presiure in anehthetized. Iiormoterisive clog\. Thc hypotensive activity v:iried its to magnitudc and duration of effect. I'or example, 1 ( 4 mg/kg ir-) p r o d ~ c d1iie:i11blood p r e t m x decraaes
CH,O'
CH,CH=CH, Yield,
a
KO.
RI
39
H
40
H
Rz COzCnHb COC.Hj
hlethod
70
h l p or bp (mm). " C
A A
58 33
171 ( 0 . 1 ) 81-82
41 H CO-2-COnHCsHd 40 All analyses were for C, H, X. b C: calcd, 64.07; found, 64.50.
Recrystn solvent
EtzO-petr ether (bp 30-60') CsHs
117-120
TABLE I11 CH,?
p
cHJo135
CH,O
CHLCH=CH,
Yield,
M p or h p
No.
n
Method
70
(mm). OC
43 43 44 45
CH3 CHzCHGHi CH=CHCeHj CaHj
C C C C
45 55 10
146 144 91-93 114-115
46
2-C,HaS
All analyses were for C, H, IC.
73
Recrystn sol! ent
EtCOJle C6Hs
EtzO
Petr ether (bp 30-60') C 32 138-140 EtOH C: calcd, 68.73; found, 60.19. C: calcd, 74.73; found, 74.23.
of 44 to SO mm,. lasting up to 1 hr. Compounds 3, 27, and 29 at 4-S mgllig iv produced decreases of 20 to 40 mm hich were too brief (1-3 min) in duration to be of interest. The parent compound 1 was also studied in unanesthetized renal hypertensive dogs (Grollnian technique) to compare its activity to two standards, hydralazine and reserpine. The drugs were given orally in gelatin capsule>. At a dose of 25 mg/kg, 1 produced a maximum decrease in systolic pressure of 23 mm, compared with hydralazine (5 nig/lig) which produced a 65 mm decrease, and reserpine (10 mg/kg) which produced a 30 mm decrease. The maximum decrease obtained in control dogs (empty capsule) was 11 mm. Thus, 1 appeared to be less potent than hydralazine, and to posses mild hypotensive activity. The most extensive evaluation was done n i t h 2, since this compound had activity in renal hypertensive rats and anesthetized normotensive dogs which was comparable with that of 1 together with preliminary wutP toxicity in mice, rats, and dogs which suggested that it was less toxic than the parent compound. I n renal hypertensive rats a single oral dose of 125 nig/lig of 2 produced n maximal depressor response of :ipproximntely 30 mm below control levels, with a duration of S to 12 hr. h multiple dming schedule of 12,; nig/lig 3 times daily a t 4-hr intervals, for 3 days, produced no apparent tolerance to the antihypertensive effect of the compound. I n renal hypertensive dogs the minimal effective dose of 2 was 50 mg/kg PO. The onset of action was within 1 hr, a maximal decrease of 30 to 3.3 mm occurred a t 2 hr, and the total duration was approximately 3 hr. Higher doses (100 and 200 nig/l,g) exerted about the mnie magnitude of responses, but the duration was 6 hr or longer. However, symptoms consisting of lacrimu-
tion, vasodilation, and emesis were observed in some dogs at these higher doses. The effects of 2 were also determined on several cardiovascular parameters in pentobarbital anesthetized, normotensive dogs. The compound was dissolved in 0.9% saline and infused into a femoral vein over a 1-min period. TAHLI.: I\' 1 1 i . r i ~ i , ; s E s T . \ i ~ I V EC.~RDIOV.WX-L.\R EFFECTS OF
2 Parameter
IX hES1'HtTIZb:D
---1\laximum 1 mg/kg
DOGS
per cent change after Za_-. 4 mgkg 8 mdkg
Mean arterial blood -4 ( h 3 ) -26 ( f 5 ) -67 ( f 4 ) pressure Heart rate -*5(f8) - 1 7 ( f 2 ) -12(&14) Cardiac output* -9 ( 1 9 ) +Y(f2) -10(+17) +8(ill) -7(+5) -6O(f10) Peripheralvascular re& taiicec Alean values (+ std error) of 3 or 4 dogs. b Dye-dilution techniqne. c Peripheral vascular resistance = mean arterial blood presswe (mm) 'cardiac ontput (I, lmin).
Table I V contains a summary of the results a t 1, 4, and S nig/lig iv. The onset of hypotension was immediate arid the maximal response was seen within 5 min. Thereupon the blood prehsure gradually rcturned to control levels. Total duration of efTect varied with the dose; higher doses produced effects lasting 1 hr or more. Heart rate was slightly to moderately reduced after doses of 4 to 8 mg/kg. Cardiac output was variably, but not markedly altered. Peripheral vascular resistance was greatly decreased after S mg/kg of 2. I n order to obtain an indication of the possible mechanism of the hypotensive effect, blood pressure responses
at room temp 48 hr. The mixture w-as filtered, the filtrate coned in vacuo, and the residue recrystd from CeHs: yield 92.5 g S-Morpholinoacetyl-l-(3,4,5-trimethoxybenzyl)-3-buteny~- (73%); mp 130-132". Anal. (CljH19S04) C, H, N. ~~-Carbomethoxy-l-(3,4,5-trimethoxybenzy~)-3-butyny~amine. amine (18j.-The reaction was carried out as in the preceding -To a solutionof 13.9 g (0.05mole)of 2-(3,4,5-trimethoxybenzyl)example using morpholine in place of S-methylphenethylamine. 4-pentynaniide in 150 ml of MeOH w-as added a solutioii of 2-(3,4,5-Trimetho~yphenyl)-4-pentenonitriIe.-~4 solution of SaOCl prepared from 0.3 mole of XaOH, 0.1 mole of Cl?, and 65 10.4 g (0.05 mole) of 3,4,5-trimethoxyphenylacetonitrilein 100 ml ml of ice-H20. The mixture \\-as refluxed 1hr and concd in e'acico of P h l l e was added dropwise. t o a stirred, cooled mixture of 2.0 g to remove lIeOH and the aqlayerwasextractedwithEt2O. The (0.05 mole) of KaSHn and 100 ml of Phhle under S2. The mixEt20 extract was wa.5hed with 5:; HC1, H20, dried over LIgSO,, tlire was stirred a t room temp for 1.5 hr. After the dropwise concd t o 0.5 volume, cooled, and filtered: yield 7.6 g ( . j O y c ) : additiotl of allyl bromide (7.3 g, 0.06 mole) the reaction mixture mp 90-91". Anal. (CiGH2iNOj)C, H, K. was refluxed 3 hr, cooled, aiid treated, dropwise, with 200 ml of S-Methyl-1-(3,4,5-trimethoxybenzyl)-3-butynylamine HydroHtO. The Ph3Ie was dried (NatS04) and concd in vacuo and the residm distd: yield 11.7 g (9.jcz); bp 137-141" (0.1mm); T L ~ ~ D chloride.-S-Carbo1nethoxy-l-(3,4,5-trimethoxybeiizyl)-3- butyiiylamine (10 g , 0.03 mole) was reduced by the procediire de1.fj31.j. zlnal. (C,4H1in'03) H, N; C : calcd, 6S.00; found, &bed in method B: yield 4.7 g ( 4 7 5 ) ; nip 173-174". .L~ial. 67.26. (CisHmNOa.HC1) 2-(3,4,5-Trimethoxyphenyl)-4-pentenylamine.-The amine v a s ~..~ , C, , H. , S. ,$--(2-Carboxybenzoy1)-1-(3,4,5-trimethoxybenzyl)-3-butenylprepared by LAH reduction of 3-(3,4,5-trimethoxypheny1)-4amine (23).-A mixt,ure of 25.1 g (0.1 mole) of 1-(3,4,5-trinieperitenonitrile (0.033 mole), using the procedure of met'hod B : (1, base), 14.8 g (0.1 mole) of yield 18.2 g (73%); bp 127-130" (0.1 mm). Anal. ( C I ~ H ~ I S O ~thoxybenzyl)-3-butenylamiiie ) phthalic anhydride, and 500 nil of dioxane was refluxed 10 rnin H : C: calcd, 66.91; found, 66.30. and concd in t'acuo. The residue was recrystd from MeOH. The maleate salt. was prepared in IPX-Et20, mp 124-126" dec. S-~2-Carboxybenzoyl)-2-(3,4,5-trimethoxybenzyl)-4-pen.Lna/. (C14H2,SOi)H ; C : calcd, 58.85; found, 58.19, S-Carbethoxy-2(3,4,5-trimethoxyphenyl)-4-pentenylamine. tenylamine (41).-The reaction x a s carried out as in the preced-A mixture of 8 g (0.03 mole) of 2-(3,4,5-trimethoxyphenyl)-4- ing example using 2-(3,4,5-trimethoxybenzylj-4-pentenylamine. 1 S-[5-(3,4,5-Trimethoxyphenyl)-l-penten-4-y1] phthalimide penteriylamine, 4 g (0.04 mole) of EtZT, and 250 ml of Et20 was (36).-A mixture of 26 g (0.06 mole) of S-(2-carboxybenzoy1)-1stirred, cooled, and treated, dropwise, with 4 g (0.04 mole) of (3,4,5-trimethoxybenzyl)-3-butenylamiiie(23) and 300 ml of ethyl chlorocarbonate. The reaction mixture was stirred 1 hr a t xylene was stirred aiid refluxed 4 hr. During this period, the room temp and filtered and the filtrate was concd. The residue theoretical amount of H2O collected ill an attached Dean-Stark u was distd: yield8 g (77c;): bp 165-173' (0.1 mm); n 2 ~ 1.5265. trap. The mixture was coned and the residiie recrystd from dnal. (CiiHzjSOj) C, H, K. LIeOH-H20. Ethyl 2-(3,4,5-Trimetho~ybenzyl)-4-pentynoate.-~4 mixture S-[5-(3,4,5-Trimethoxyphenyl)-l-penten-4-yl] -3,4,5,6-tetraof 6.9 g (0.3 g-atom) of T a aiid 300 ml of EtOH was stirred at 0" chlorophthalimide (37).-A mixture of 23 g (0.09 mole) of 1-(3,4,5rintil all S a had reacted. Ethyl 2-propargylacetoacetate, 55 g trimethoxybeazyl)-3-butenylamine(1,base), 26.2 g (0.09 mole) of (0.32 mole), dissolved in 100 ml of EtOH was added dropwise to 3,4,5,6-tetrachlorophthalic anhydride, and 150 ml of xylene was the reaction mixtlire aiid stirring at 0" was continued for 1hr. A stirred and refluxed in a flask fitted \\-ith a Dean-Stark trap. solution of 64.X g (0.33 mole) of 3,4,5-trimethoxybenzyl chloride After a 2-hr period, the theoretical amount of H20 had been in 300 ml of EtOH was added, dropwise, and after stirring for 1.3 collected, the react'ion mixtiire was coiicd and recrystd from hr, the mixture was refluxed 2 hr and filtered and the filtrate was i-PrOH. coiicd in w " o . The residue was extracted wit'h EtlO, the Et& solution was washed with H20, dried, concd, and the residue was 2-(3,4,5-Trimethoxybenzyl)-4-pentenonitrile.-Amixture of distd; yield 20 g (205,); bp 175" (0.2 mni). Anal. (C1752 g (0.19 mole) of 2-(3,4,5-trimethoxybeiizyl)-Ppentenamide and 1400 ml of PhMe was stirred while 154 g (1.0 mole) of POC13 Hp?Oj) H ; C: Calcd, 66.63; found, 65.76. was added during a 20-min period. The reaction mixture was 2-(3,4,5-Trimethoxybenzyl)-4-pentynoicAcid.--A mixture of 230 g (0.75 mole) of ethyl 2-(3,4,5-trimethoxybeiizyl)-.l-penly- refluxed 3 hr and coricd in vacito. The residue was mixed with ice-H20 and the product extracted (EtsO). The dried (1\IgS04) iwate, 470 g (0.75 mole) of KOH, 1.8 1. of H20, aiid 2 1. of EtOH extract was concd and the residue distd: yield 41.2 g ( 8 5 5 ) ; was refluxed 16 hr. The mixture \\-as concd to remove the EtOH bp 156-138" (0.3 mm). Anal. (C15H19h'OJ)H, T; C : calcd, :tiid the aq solution was cooled aiid acidified with coned HC1. 6X.94; found, 68.45. After extraction with EtsO, the extract was dried (1\IgS04), 2-(3,4,5-Trimethoxybenzyl)-4-pentenamidoximeHydrachlovoiicd t o a voliime of 200 ml, cooled, and filtered: yield 133 g (64r;); nip 113-114'. Anal. (CljHlaOj) C, H. ride.-A mixture of 17.2 g (0.07 mole) of 2-(3,4,5-trimethoxybeiizyl-4-pentenonitrile, 11.5 g (0.17 mole) of S H 2 0 H.HC1, 7.0 g 2-(3,4,5-Trimethoxybenzyl)-4-pentynamide.-To a solution of 50.3 g (0.46 mole) of ethyl chloroformate in 600 ml of CHC13 main(0.07 mole) of Sa2C03, 75 ml of H,O, and 75 ml of EtOH was tained at -00" \\-as added, dropwise, a mixtlire of 129 g (0.40 heated at 70" for 24 hr. The reaction mixture \\-a,
