Journal $Medicinal Chemzstry 0 Copyright 1974 by the American Chemical Society
Volume 17, Number 11
November 1974
Compounds Related to 4-Diisopropylamino-2-phenyl-2-( 2-pyridy1)butyramide.Their Synthesis and Antiarrhythmic Activity Chung H. Yen,* Harman S. Lowrie, and-RichardR. Dean Departments of Chemical Research and Biological Research, Searle Laboratories, Chicago, Illinois 60680. Received April 1, 1974
Modification of the carboxamide group of 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide (1, a new antiarrhythmic agent) resulted in compounds which possess considerable antiarrhythmic activity.
4-Diisopropylamino-2-phenyl-2-( 2-pyridy1)butyramide (1, disopyramide) is a potent antiarrhythmic agent first described by Mokler and Van Armanl and subsequently shown by K a t 9 and Dreifus3 to be a clinically useful alternative to quinidine. The tetrazole and oxadiazole analogs of l have been reported by A d e l ~ t e i n .This ~ report describes the synthesis and antiarrhythmic activity of the corresponding hydrazides, monosubstituted amides, their thio analogs, and some related compounds.
Erhart and coworkers have reacted sodium or phenylsodium with 3-phenyl-3-(2-pyridyl)propylamines (compounds homologous to 2) to obtain the corresponding Na salts from which esters and ketones homologous to 7a,b and 3 have been ~ r e p a r e d In . ~ our work 2 was lithiated with n-BuLi in a hexane-ether solution. Treatment of the Li salt of 2 with methyl acetate, oxygen,6 benzyloxyamine,' carbon dioxide, and alkyl chloroformates afforded, respectively, 3, 4a, 5a, 6, and 7a,b. Reaction of lithiated 2 with carbon disulfide furnished the lithium salt of a dithio acid that with methyl iodide afforded 8. Addition of lithiated 2 to ethyl chlorothiolformate in ether a t -70" afforded 9, but inverse addition a t - 4 to -2" afforded the dimer 10 (Scheme I and Table I).
IVJ
Scheme I 1
Chemistry. At first we tried to prepare the hydrazide and the thioamide corresponding to 1. Reaction of the ethyl ester 7b with hydrazine under a variety of conditions failed to yield the hydrazide. Likewise, attempts to prepare the thioamide from 1 yielded, in order of increasing severity of conditions and reagents, starting material, dehydration to the corresponding nitrile, cyclization to various substituted pyrrolidones or cleavage to 2; the nitrile behaved similarly.? We concluded t h a t steric hindrance prevented the usual conversions and we sought different routes for preparing these compounds. From this search many other analogs were also obtained. The key intermediate 2 was most conveniently prepared by the hydrolysis and decarboxylation of 1 (eq 1).
,
aqHSO,
[RCO,H]
(unstable)
-
RH
, A - R O R4a, ' R' = H
$ 5 , b, R ' = A c
b, R'=Ac_ RCOR4
7a. R,' = CH,
cs
:RJ=CIH, RCS,Li
9, R4=SC,Hj 10, R4 = R
(l)
2
@-& I
CCH,CH2N[CH(CH,),], throughout the text
R=
CICOSC-H,
// \\
t H S Lowrie, Searle Laboratories, unpublished work
1131
The thio hydrazide 11 was prepared by heating 8 with hydrazine in T H F (method A, Scheme 11) while the hydrazide 12a was obtained by refluxing methyl ester 7a with 85% hydrazine hydrate in methanol (method B, Scheme 11). Two derivatives of 12a were prepared: N-acetyl derivative 12b and hydrazone 12c (Table I€). Unfortunately, substituted hydrazides could not be prepared by heating methyl ester 7a with substituted hydrazine, probably due to steric hindrance. Yang has reported
2 3 4a 4b 5a 5b 6
H COCH, OH OAc
39 27 5Zb 11 12 80 24
L
2"
NHAc CO2H
M
N
124- 127 (0.2) 90- 102 (0.03) 86-88 156-160 (0.1) 160-168 (0.2) 104- 106 90-91.5
C20H28N2 C22H30N20
cz OH2BN20 C22H30NZ02 C20H29N3
C22H31N30
CZ1H28N20Z (C
7a 7b 8 9 10
0
77 74 7Ih 75b
141-158 (0.6) 156-158 (0.2)
50
146- 147.5
22
-
-C,H,,)~NH C. H, N
30N202
C23H32N202
N
c4 1H54N40
H, N ; Cd
185- 195 (0.5)
UL, CzHSOH-HzO; M, ether-Skellysolve B; N, CHzClz-n-pentane; 0, CHzClz-Skellysolve B. hYield of crude product. C: calcd, 77.1%: found, 77.65. dC: calcd, 79.57; found, 79.13. (
Table 11. Hydrazides CY=X I
Compd
X
Y
11 12a 12b 12C 13 14
S 0 0 0 0 0
NHNHZ NHNH, NHNHCOCH, NHN=C(CH3)2 NHNHCH, NHN(CH,),
15
0
N(CH,)N(CH,):,
Crystn solvent'
Yield,
P P P P
35' 47 54 72
Mp o r bp (mni), 'C
@ IC
Method
Formula
Analyses -
A
44
87-90 66-68 117- 119 104.5-106.5 176-180 (0.2) 70-75
19
175-205 (0.1)
D
70
Q
(lP,ether-n-pentane; Q, CHsOH-ether. "Yield
8
C C
C, H, cZ 1H 3 0 N 4 0 C, H, C23H32N402 C, H, C24H34N40 C, H, C22H32N40 C, H, C Z , H ~ ~ N ~ O * ( C O ~ HC, ) , .H, CHSOH C24H36N40 C, H, 2 l H 3 ON4
N, S
N N N N N N
of crude product.
successful aminolysis of hindered esters with the lithium derivative of amines8 and this method was extended to the hydrazinolysis of the methyl ester 7a to yield the alkylated hydrazides 13 and 14 (method C, Scheme 11). However, the trimethyl hydrazide 15 was prepared from phenylacetyl chloride by the two-step sequence of method D, Scheme 11. These hydrazides are listed in Table 11. Yang's method of aminolysis was also applied to prepare several N-alkyl and N-aryl derivatives (17-20) of 1 (method C, Scheme 11). However, the N-methylamide 16 was prepared by heating the thiol ester 9 with methylamine in 2-propanol, indicating that 9 is a useful active ester (method E, Scheme 11). The N-methylolamide 21 was prepared by refluxing 1 with formaldehyde in aqueous ethanol (method F, Scheme 11). The thioamide 22 was prepared by heating the dithio
ester 8 with ammonia in THF a t 60" (method G, Scheme II), but a t 100" the corresponding nitrile was the only product. The monosubstituted amides and thioamide are listed in Table 111. Biology. Multifocal ventricular tachycardia was induced in anesthetized dogs with intravenous injections of ouabain as described by L u c ~ h e s i this ; ~ method minimizes mortality from ouabain overdosage. Compounds were given intravenously a t 7 2 0 mg/kg and rated active if normal sinus rhythm supervened for a t least 15 min in a t least half of the dogs. Active compounds were then tested in dogs subjected to a two-stage ligation of the anterior descending coronary artery.I0 On the first postoperative day these dogs exhibite-d arrhythmias analogous to those observed in man following acute myocardial infarction. Compounds given intravenously a t 720 mg/kg were rated
Journal ofMedicinal Chemistry, 1974, Vol. 17, No. I 1
4-Diisopropylamino-2-phenyl-2-(2-pyridyl) butyramide
1133
Table 111. Amides CY=X I
Compd
X
16 17 18"
0 0 0
19"
0 0 0 S
20"
21 22
Crystn
Yield,
solventb
%
NHCH, NHC2HS NHC6H5
R P
67 63 29
88-90 89.5-92 184-186 d e c
E C
C22H3l N 3 0
C
NH-2-C5H,N NH(CHz),N(CH,)z NHCH20H NH2
Q
37 73 39 57'
200.5-202 d e c 174-180 (0.1) 94-96 113-115
C C
C2,H,,N3O*H,PO4. 0.5H20 C2gH32N40°H,P04
Y
S
P 0
Mp o r bp ( m m ) , "C
Formula
Method
Analyses
C23H33N30
C22H31N302
H
C21H29N3S
C, H, N
c, H, N c, H, N,
C25H38N40
G
c , H, N c , H, N C, H, N
0 C, H, N, S
QEtherwas used as solvent. bSee footnotes a, Tables I and 11; R, n-pentane; S, CZHSOH.CCrude yield.
Table IV. Antiarrhythmic Activities
Scheme I1
RCS,CHl
method A
RCSNHNHl
8
11 method B
RCoLCHl
7a
ZNH,
Compd
eRCONHNHz 12a
method C
1 BuLi
2. RCO?CH,
18 10
RCONHZ 13, Z
15
= NHCH,
Z = N(CHJ, Z = C2H5 Z = phenyl Z = 2-pyridyl Z = CH,CH2N(CHJ)z
L NaKH
RCON(CHJN(CH3k RCOSCJH,
method E NH,CH, +
RCONH,
15
RCONHCHJ 16
9 method F CH,O +
RCONHCH20H
1 RCSjCH,
8
" 1=1
1*H,P04 17 22 13
7b 12b 3 10 12a 5b 11 12c 14 7a 21
25 27 60 35 22 20 51 18 32 17 2 1 12 15 10
