J. Med. Chem. 1988, 31, 2289-2296
2289
Synthesis and Pharmacological Properties of “Soft Drug” Derivatives Related to Perhexiline Gilbert Marciniak,’ Dominique Decolin,t GBrard Leclerc,*pt Nicole Decker, and Jean Schwartz Institut de Pharmacologie (UA 589 CNRS), Dlpartement de Pharmacochimie, Facultl de Mldecine, 11 rue Humann, 67000 Strasbourg, France, and Facultl des Sciences Pharmaceutiques et Biologiques (UA 597 CNRS), 30 rue Lionnois, 54000 Nancy, France. Received May 3, 1988 In the hope of reducing the toxicity of perhexiline, a series of 27 cyclohexylaralkylaminesI1 based on the “soft drug” concept and incorporating an amide function were synthesized. In a preliminary screening, compounds were evaluated for their a-adrenolytic activities. Several derivatives, especially N-(cyclohexylphenylmethyl)-2-(cyclohexylmethy1amino)acetamide (3), N-(cyclohexylphenylmethyl)-2-(homoveratrylmethylamino)acetamide(7), and N- [2(cyclohexylamino)ethyl]-a-cyclohexylbenzeneacetamide(23) had the same activity range as perhexiline in vitro in rat aorta strips. The in vitro metabolism of these three molecules was then investigated and compared to that of perhexiline. The effect upon the a-adrenolytic activity of introducing various N-aralkylamine groups on I1 was examined. Structure/activity relationships are discussed.
Angina pectoris is one of the most frequent clinical syndromes associated with ischemic heart disease, due to an imbalance between myocardial oxygen consumption and supply. The main therapeutic agents used to treat this disease are nitrates, /3-blockers, and calcium channel blockers.l$ Perhexiline maleate belongs to the latter class of compounds and is sometimes classified in the aralkylamine s ~ b g r o u p . Its ~ mode of action remains unknown. Perhexiline is effective in treating angina4 but its use is limited by its side effects such as hepatot~xicity,~ weight loss,6 and peripheral neuropathy.’ These undesirable effects might be related to slow metabolism and accumulation of the molecule in these patients.8 Leclerc et a1.: hoping to reduce these side effects, reported in a previous paper a series of cyclohexylaralkylaminederivatives related to perhexiline. Several of them were more active than perhexiline, but they displayed chronic toxicity similar to that of perhexiline.’O We thought that the “soft drug” approach developed by Bodor”J2 could be applied to this problem. “Soft drugs” can be defined as “biologicallyactive chemical compounds (drugs) which might structurally resemble known active compounds (soft analogues) or could be entirely novel types of structures, but which are all characterized by a predictable in vivo destruction (metabolism)to non-toxic moieties, after they achieve their therapeutic effect. The metabolic disposition of the soft drug takes place at a controllable rate in a predictable manner.” Starting from this principle, and on the basis of work from our laboratory, we decided to synthesize molecules of general structure I1 (Chart I), to evaluate some of their pharmacological properties, and to investigate the in vitro metabolism of those which present the best a-adrenolytic activity. We chose first an amide function (CON< or >NCO) in A as the labile center. This function was expected to give a good compromise between chemical stability and in vivo degradation. We varied the nature of X, which was either a primary, secondary, or tertiary amine, or a heterocycle, such as the imidazolyl or imidazolinyl rings that are present in some a-adrenolytic compounds, e.g., phentolamine or RS 21361.13 Chemistry The compounds prepared in this study are listed in Table I and their syntheses are shown in Schemes I-VI. The reaction of a-cyclohexylbenzenemethanamine (28) with the appropriate chloroalkanoyl chloride gave the chloroalkylamides 29a-c (Scheme I), which were treated f
Facult6 de MBdecine. Facult6 des Sciences Pharmaceutiques et Biologiques. 0022-2623/88/1831-2289$01.50/0
Chart I
I (perhexiline)
I1
A = labile group that must control the metabolism; X = amino group or heterocycle group (imidazolyl, imidazolinyl); n = 1-3
with the requisite amine, with or without solvent (methods A, B, and C)to give compounds 1-7, 13, 14, and 17. N-Methylamide derivatives 11 and 12 (Scheme 11) were prepared in an identical manner to Scheme I except that the initial amine was N-methyl-a-cyclohexylbenzenemethanamine (31),which wm prepared in three steps from the commercial ketone 30, in a 67% yield. The synthesis of 18 (compound I1 with A = NHCO and n = 1)is shown in Scheme 111. It involved the formation of 34 from acid 33, which was converted to the hydrochloride salt and hydrogenated over Pt02 (method D). For the synthesis of compounds 22-25 (A = CONH), two pathways were used, as shown in Scheme IV. The first (method E) involved the formation of the acylaziridine 35, which was then readed with a secondary amine in acetone. When cyclohexylamine was used to synthesize 23, compound 36 was the major product isolated (56%), as was Charlier, R. Antianginal Drugs; Springer-Verlag: New York, 1971. Winbury, M. M.; Abiko, Y. Perspectives in Cardiac Vascular Research; Raven: New York, 1979; Vol. 3. Spedding, M. Trends Pharmacol. Sci. 1985,3, 109. Teo, K. K.; Kelly, J. G.; Darby, J. F.; Ennis, J. T.; Horgan, J. H. Clin. Pharmacol. Ther. 1983,34, 744. Howard, D.; Russel, J. Br. Med. J. 1976, 1, 133. Pilcher, J. Postgrad. Med. J. 1978, 54, 663. Lhermite, F.; Fardeau, M.; Chedru, F.; Mallecourt, J. Br. Med. J. 1976, 1, 1256. Shah, R. R.; Oates, N. S.; Idle, J. R.; Smith, R. L.; Lockhart, J. D. Br. Med. J. 1982, 284, 295. Leclerc, G.; Decker, N.; Schwartz, J. J. Med. Chem. 1982,25, 709. Foncin, J. F.; Vu-Ngoc Huyen, D.; Cathala-Jacquier, F., Synthelabo Laboratories, Internal Report. Bodor, N. Trends Pharmacol. Sci. 1982,3, 53. Bcdor, N.; Oshiro, Y.; Loftsson, T.; Katovich, M.; Caldwell, W. Pharmacol. Res. 1984, 3, 120. Timmermans, P. B. M. W. M.; Van Zwieten, P. A. J. Med. Chem. 1982,25, 1389. 0 1988 American Chemical Society
Marciniak et al.
2290 Journal of Medicinal Chemistry, 1988, Vol. 31, No. 12
also observed by Thyrum and Day.14
i 0
36 -
However, 23 could be obtained by using excess cyclohexylamine (method E'). The second pathway (method F) was via the N-(2-chloroethyl)amide derivative 37. Synthesis pathways for compounds 11, where A = NHCO and X represents either an imidazoyl or an imidazolinyl group, are described in Scheme V. Cyanoalkylamides 38a,b were obtained by heating 29a,b with NaCN in DMSO and transformed to their corresponding imidate hydrochloride (HCl, EtOH).15 Without purification, these salts were reacted either with ethylenediaminel6 (method G ) to give the corresponding 2-imidazolinyl derivatives 8 and 15 or with aminoacetaldehyde diethyl acetal followed by acid-catalyzed hydrolysis and ring closure" to give the 2-imidazolyl derivative 16 (method H). However, only traces of 9 were obtained with this procedure, so finally 9 was produced by reacting 28 with N-benzyl-2imidazoleacetic acid ethyl ester, 39 (prepared by ethanolysis of N-benzyl-2-(~yanomethyl)imidazole),'~ followed by hydrogenolysisof adduct 40 (method I). The Csubstituted imidazole 10 was prepared by heating 28 with ethyl 4imida~oleacetate'~ 41 in a sealed tube at 190 "C for 24 h (method J). Scheme VI shows the synthesis of compounds 11,where A = CONH and X = imidazolyl or imidazolinyl. Nitriles 42a,b were prepared with the Schotten-Bauman procedurem and transformed as described in Scheme V to give 19, 26 and 20, 27. Coupling 31 with 4-(aminomethyl)imidazole,2143, by a standard procedure,22 gave the 4substituted heterocycle 21 at a 34% yield (method K).
Results and Discussion The cyclohexylaralkylamides described in this study were initially tested for their a-adrenolytic activity. On rat aorta (see the methods section), several of those compounds tested (3,7, and 23; see Table I) show a-adrenolytic activities comparable (pA2 6.6) to that of perhexiline (pA2 = 6.7),confirming the modest influence of the labile group upon this activity. Similarly, converting the CONH into a NHCO group has little effect, as is shown by comparing the couples 13 and 23,8 and 19,9 and 20, and 15 and 26. In the NHCO series, the N-methylation of the amide link reduced the activity, thus 2 > 11 and 3 >> 12. As far as the length of the side chain was concerned, the activity was n = 1 > 2 3; thus 2 > 13 17. The presence of a secondary or tertiary amine increased the activity; thus 3 = 2 >> 1. Introducing various N-aralkylamine moieties
rl
r
0 5 1 0 1 5
TINE (MINUTES)
b
J -0
J L
5
10
E
0
5
1
0
1
5
TIHE (MINUTES)
Figure 1. Chromatographic profiies obtained for 3 (a) and 7 (b), before (left) and after (right)incubation (30 min) with rat liver
microsomes.
-
-
-
Thyrum, P.; Day, A. R. J. Med. Chem. 1965,8,107. Houben, J.; Pfankuch, E. Chem. Ber. 1926,594 2397. Klarer, W.; Urech, E. Helv. Chim. Acta 1944,27, 1762. Caroon, J. M.; Clark, R. D.; Kluge, A. F.; Olah, R.; Repke, D. B.; Unger, S. H.; Michel, A. D.; Whiting, R. L. J. Med. Chem. 1982, 25, 666. Kornfeld, E. C.; Wolf, L.; Lin, T. M.; Slater, I. H. J. Med. Chem. 1968,11, 1028. Pyman, F. L. J. Chem. Soc. 1911,99, 668. Goldberg, A. A.; Kelly, W. I. J. Chem. SOC.1947, 1369. Bastiaansen, L. A. M.; Godefroi, E. F. J. Org. Chem. 1978,43, 1603. Konig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
0.1
US
0.2
IO6 M
Figure 2. Doublereciprocal plots used to compute K,,, and V,, for 3 (A) and 7 (A).
found in several potent a-adrenergic gave moderately active compounds 5,6,7, and 14. The presence of an imidazolyl or imidazolinyl ring has no clear positive effect. Thus, for n = 1, 8 = 9 but for n = 2, 15 > 16. In the CONH series, compounds displayed the same activity, whatever n was. Surprisingly, here the activity was highest for the secondary amine derivative 23. The morpholino derivative 25 was ca. 30 times less active than (23)
Leclerc, G.; Decker, N.; Schwartz,J. Arzneim.-Forsch. 1985,35,
1357. (24) Decker, N.; Quennedey, M. C.; Rouot, B.; Schwartz, J.; Velly, J. J. Pharm. Pharmacol. 1982, 34, 107. (25) Ariens, E. J. N. Y. Acad. Sci. 1967, 139, 606.
"SoftDrug" Derivatives Related to Perhexiline
Journal of Medicinal Chemistry, 1988, Vol. 31, No. 12 2291
Scheme I"
a
R-NH,
28
-
0
R-NH
29
II
b
-C-(CH,)n-Cl
II
R-NH-C-(CH,)n-X
M e t h o d A,B.C
a,n
0
=1
-t o l ,
13,14 a n d a
1
b,n=2
c,n =3
" (a) Cl(CH,),COCl, EbN; (b) XH (Et,N); for the definition of X, see Table I. Scheme 11" CH, I R-N-C-CH,-N
a . b.c
I
I'
R-NH-CH,
R-N-C-CH,-CI CH, I
d
___)
\
II
31
-11
/ Method B O
0
32
H
CH, I R-N-C
,CH3 -CH,-N
11
0
30 -
12 -
'0
"For definition of R, see Scheme I. (a) NaEiH,; (b) PBr,; (c) methylamine; (d) ClCH,COCl; (e) cyclohexylamine; (f) N-methylcyclohexylamine. Scheme 111" A-COOH
a.b
H
R-CO-NH
33
@
c.d
R - C O - N H 6
,HCI
Method D
34
18 -
"For definition of R, see Scheme I. (a) SOCl,; (b) 2-aminopyridine; (c) 1 equiv of HCl; (d) H2/Pt02. Scheme IV" 0
II
*-/
Method E . € '
35 R -C
R -COOH
- NH-CH,-CH,22, X
R a.c
X
= -N(CH,-CH,),
-C -NH-CH,-CH,-CI 37 -
Method F
23, X=-NH 24, X
-
= --N
3
" For definition of R, see Scheme I. (a) SOCl,; (b) aziridine, KOH; (c) 2-chloroethylamine hydrochloride, Et8N (d) the piperidine analogue 24. As before, the 4-substituted imidazole derivative, 21, had a very low activity. In conclusion, several of the compounds in this study had interesting a-adrenolytic activities, of the same order as perhexiline. As previously indicated, the undesirable effects of perhexiline might be related to slow metabolism and accumulation. As compounds 3, 7, and 23 show aadrenolytic activities comparable to that of perhexiline,
the question still remained to know whether these compounds are metabolized more actively than perhexiline. In a previous work,%we have shown that perhexiline was not metabolized by rat liver microsomes. This result was in accordance with the accumulation of the molecule ob(26) Decolin, D.; Batt, A. M.; Ziegler, J. M.; Siest, G. Biochem. Pharmacol. 1986,55, 2301.
2292 Journal of Medicinal Chemistry, 1988, Vol. 31, No. 12
Scheme Va
29 a.b
a
Marciniak et al.
-
0
II
b c
R-NH-C-(CH,),--CN
0
R-NH-C-(CH,),
Method G
38 a , -
n= 1
b. n = 2
8 , n=l -
H
15, n = 2
Method H
16, n = 2
39
40
Bz
H
Bz
9 -
10 -
41 -
aFor definition of R, see Scheme I. (a) NaCN; (b) EtOH, HCl; (c) H2NCH,CH2NH2;(d) HzNCHzCH(OEt)2;(e) 2 N HC1.
Scheme VIa
20 . n = 1 21 , n = 2
33 -
+
(>cH2-NH2
.2Hci
DCC , HOBT, Et,N
h
0 R-C-NH-CH,
