J. Med. Chem. 1982,25, 709-714
709
Synthesis and Cardiovascular Activity of a New Series of Cyclohexylaralkylamine Derivatives Related to Perhexiline GBrard Leclerc,* Nicole Decker, and Jean Schwartz Znstitut de Pharrnacologie et de Mgdecine ExpGrimentale, Facult; de Mgdecine ERA 142, U. 206, Universit6 Louis Pasteur, 67000 Strasbourg, France. Received September 4, 1981
A series of 24 cyclohexylaralkylamine derivatives related to perhexiline has been synthesized and screened for cardiovascular activity. All the compounds contained an exocyclic amine which was substituted either by an alkyl, cycloalkyl, or aralkyl group. In the hope of further reducing toxicity, the synthesis of p-tolyl- and p-hydroxyphenyl derivatives 23 and 24 was undertaken. The effect of separating the cyclohexylamine moiety with respect to the aromatic nucleus has been systematically examined. The pharmacological investigations were directed to a search for compounds having an activity better than perhexiline according to the following order of criteria: (1)a-adrenolytic activity; (2)increase of coronary blood flow; (3) calcium antagonism. Several compounds were more potent and exhibited lower toxicity than perhexiline. Further detailed pharmacological investigations (tension time index and (3) for clinical trials, which decreased cardiac work) have led to the selection of N,2-dicyclohexyl-2-phenethylamine are now under way. Effective antianginal drugs are still needed owing to the ever increasing number of patients suffering from heart diseases. Perhexiline maleate [Pexid, 1,l-dicyclohexyl2-(2-piperidyl)ethane (I)],l recently introduced in the market in Europe, has proven to be very effective in the treatment of angina p e ~ t o r i s , ~although “ its mechanism of action remains unknown.
11. n = 0 - 4
I.
Perhexiline
However, it is of somewhat limited interest because of the hepatotoxicity: weight loss: and peripheral neurop a t h ~which ~ it induces. Singlas et al.* proposed that patients developing peripheral neuropathy metabolize the drug more slowly than those patients who do not show this side effect. In the hope of reducing the serious adverse effects of perhexiline, we thought that it would be of interest to examine the activity of compounds of general formula 11 in which the secondary amine group is “exocyclic”. In the light of the work of Singlas, we have also examined the influence of introducing an aromatic ring (Rl, R2, R3, or R4 = aryl) on the biological activity. In this article, we describe the synthesis of 24 derivatives of general formula I1 and some of their cardiovascular properties. Chemistry. Compounds of type A (general formula 11, n = 1) were prepared according to Scheme I, which involves as a main step the reduction of an amide intermediate with BHS/Me2S. The hydrogenation of the aromatic (1) W. J. Hudak, R. E. Lewis, and W. L. Kuhn, J. Pharmacol. Exp. Ther., 173,371 (1970),and references cited therein. (2) G. Ch. Schimert, In “Perhexiline Maleate”, Proceedings of a Symposium, Strasbourg, France, Sept 18,1975,Excerpta Medica, Amsterdam, 1976,pp 118-125. (3) C. G. Pepine, S. J. Schang, and C. R. Bemiller, Postgrad. Med. J., 49,43 (1973). (4) M. L. Armstrong, D. Brand, A. J. Emmett, J. L. R. Hodge, G. S. M. Kellaway, P. Mestutz, M. Reefman, and D. C. Wallace, Med. J. Aust., 2, 389 (1974). (5) D. Howard and J. Russel, Br. Med. J., 1, 133 (1976). (6) J. Pilcher, Postgrad. Med. J.,54,663 (1978). (7) F. Lhermitte, M. Fardeau, F. Chedru, and J. Mallecourt, Br. Med. J.,748,1256 (1976). (8) E. Singlas, M. A. Goujet, and P. Simon, Eur. J. Clin. Pharmacol., 14,195 (1978).
nucleus of 3 at 60 “C under 50 atm during 4 days led to 4 in 45% yield. Compounds of type B (general formula 11, n = 2), which possess a 3,3-dicyclohexylpropylaminemoiety, were prepared from 3,3-diphenylpropionic acid (Scheme 11). Catalytic hydrogenation of the carefully purified starting acid using a rhodium catalyst under 50 atm led to 3,3dicyclohexylpropionic acid, which was then converted to the amine B. Compound 15 was also synthesized from diphenylpropionic acid by careful reduction using a larger excess of Pt02 The intermediate acid was then transformed into 15 as above. Methylation of 10 via the Eschweiler-Clarke reaction gave the N-methyl derivative 11. We also prepared (Scheme 111)derivatives 16-19 containing the adamantyl group, which could be considered as an analogue of the dicyclohexyl moiety of perhexiline. T o obtain 20 (formula 11, n = 0) required a different procedure. Dicyclohexyl ketone was condensed with cyclohexylamine in the presence of Tic&. The resulting imine was then reduced under atmospheric pressure to give 20 in 38% yield. The N,4,4-tricyclohexylbutylamine21 (formula 11, n = 3) was prepared from 3,3-dicyclohexylpropionic acid using the Arndt-Eistert reaction (Scheme IV) The isolated diazo ketone was heated with cyclohexylamine in the presence of AgNO, to afford the expected amide. This was finally reduced by LiA1H4/THF in 21. The higher homologue derivative 22 (formula 11, n = 4) was prepared as illustrated in Scheme V, which involves a malonate alkylation as the main step. The 5,5-diphenylpentanoic acid obtained after saponification of the diester intermediate gave 22 in an overall yield of 28%. Of interest in this study of structure-activity relationshipse was the 4-OH derivative 23 and the 4-Me derivative 24. The synthesis of the 4-OH derivative 23 is shown in Scheme VI. Nitration of the commercially available 2phenyl-2-cyclohexylaceticacid in concentrated H2S04 between -10 and 0 “C afforded, after recrystallization from C6Hl4-CCl4, the pure p N 0 2 derivative in 55% yield. Catalytic reduction of the NOz group, followed by diazotization and decomposition of the diazonium salt in boiling dilute sulfuric acid, led to the phenol derivative. This was followed by the esterification of the acid fraction prior to the benzylation of the phenol group. After saponification, the resulting acid was heated as described previously to
.
(9) G. J. Wright, G. A. Leeson, A. V. Zeiger, and J. F. Lang, Postgrad. Med. J., 49, 8 (1973).
0022-2623/82/1825-0709$01.25/0 0 1982 American Chemical Society
Leclerc, Decker, Schwartz
710 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6
K
I
r
$1
. c
K
I I
i
CI
I
Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6 711
Cyclohexylaralkylamines Related t o Perhexiline Scheme I1
l)SOCI, 2) R-NH,
H,- RhiAl2Oo
n u v
H,/PtO,
g p
HCHOIHC0,H
N\
R R
t
= =
C,H,,
R
CH(CH,)CH,CH,C,H, CH(CH,)CH,C,H,
R =
CH,CH2C,H,-3,4(0CH,),
Scheme V
Scheme I11 /Co2H SOCI,
LiAIH,
R - NH,
16 17 18 19 -
R = C,H,, R CH(CH,)CH, CH, C,H, R = CHCH,) CH, C,H, R T CH,CH2C5H,-3,4(0CH,),
n
Scheme IV
1) SOCI,
(CH,),-NH
2) CaHll-NH, 3 ) BH,iMe,S
Y
4) H,-RhlAI,O,
u z 'C0,H
2) CH, N,
Scheme VI
3-c02H 1) "0, 2) H,/PtOz
3) NaNO, 4)
" 0 give 23 in 23% overall yield. The synthesis of 24 is depicted in Scheme VII. Tolylacetonitrile was alkylated with cyclohexyl bromide/ NaNHz in benzene, and the resulting nitrile was hydrolyzed with 48% aqueous HBr under drastic conditions (80 h, reflux). The acid thus obtained was then converted to 24 using classical methods.
3-c02H 70$ n
1) MeOHiH'"
n
1
HO
n
1) SOCI,
Biological Results The pharmacological investigations were directed to a search for compounds having an activity better than that of perhexiline according to the following order of criteria: (1)a-adrenolytic activity; (2) increase of coronary blood flow; (3) calcium antagonism activity. These biological data are shown in Table 11. Several of the compounds listed in Table I1 show higher a-adrenolytic activity than perhexiline. Examination of the alicyclic series shows the following order of potency:
20 < 4 = 10 > 21. Thus, the best activity was obtained among compounds of the general formula I1 with n = 1 or 2. This is also in agreement with the best a-adrenolytic activity exhibited by compounds of the semiaromatic series, such as 3 (& = C6H5and n = l),and to a lesser extent by 15 (R,= C6H5and n = 2). It is noteworthy that the nature of the terminal amine did not seem to play a clear
712 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 6
Leclerc, Decker, Schwartz
Table 11. Biological Properties of Aralkylamine Derivatives compd
1 2 3 4
5 6 7 8 9
10 11 12 13 14 15 16 17 18 19
dog coronary flowa 104.5 i: 46 38.5 t 12 6 2 + 10 84 f 23 157 i: 81 71.5 i: 2 7 3 t 10 100.5 f 6 1 0 5 i 55 130 t 23 67 * 3 C
42i. 13 44.5 + 27 156 + 44 9 9 t 13 2 1 5 i 128 1 4 6 i 21 133 i 55 194 + 106 95.5 i 28
20
a-adrenolytic act.:b rat aorta PA, 7.25 i 0.47 5.9 i: 1.14 7.9 t 0.15 7.25 i 0.22 6.9 t 0.21 7.6 + 0.33 7.25 + 0.28 6.0 i 0.02 6.35 i: 0.37 7.25 t 0.21 6.15 t 0.44
Ca antagonism: pig coronary PA,
