J. Med. Chem. 1986,29, 133-137
133
7-(Trifluoromethyl)-4-aminoquinoline Hypotensives: Novel Peripheral Sympatholytics John M. McCall,* R. E. TenBrink, Bharat V. Kamdar, Louis L. Skaletzky, Salvatore C. Perricone, Richard C. Piper, and Patrick J. Delehanty The Upjohn Company, Kalamazoo, Michigan 49001. Received April 15, 1985 A family of 7-(trifluoromethyl)-4-aminoquinoliiesthat are hypotensive agents and that act by a novel sympatholytic mechanism is described. Structure-activity relationships in this series have been elucidated. Some of the more [7potent hypotensives were evaluated for safety in the mouse. A candidate, 1-[(4-fluorophenyl)sulfonyl]-4-[4-[ (trifluoromethyl)-4-quinolinyl] amino]benzoyllpiperazine hydrochloride (losulazine hydrochloride) has been selected for clinical development. Losulazine hydrochloride is a hypotensive agent in the rat, cat, and dog. At acute effective hypotensive doses, it does not block the response of the sympathetic nervous system to stimuli. Both animal pharmacology and clinical experience suggest that losulazine hydrochloride may be free of the clinically limiting side effects that often plague compounds that decrease blood pressure by interfering with autonomic neurogenic function.
hypotensives. The chemistry, pharmacology, and safety We have investigated the structure-activity relationdata from this series are described below. ships, pharmacology, and safety of a family of 7-(triChemistry. Scheme I depicts the various routes that fluoromethyl)-4-aminoquinolinesthat are hypotensive we have followed to our 7-(trifluoromethyl)-4-aminoagents and that act by a novel sympatholytic mechanism. A candidate, l-[(4-fluorophenyl)sulfonyl]-4-[4-[[7-(tri- quinoline products. In method A, the 4-anilinoquinoline product 2 of the reaction of p-aminobenzoic acid and 7fluoromethyl)-4-quinolinyl]amino] benzoyl]piperazine hy(trifluoromethyl)-4-chloroquinoline~ is a convenient drochloride (losulazine hydrochloride, compound 3n;see starting material for a variety of amides of structure 3. The Table I) has been selected for clinical development. The acid was activated as the acid chloride, the imidazolide, cardiovascular pharmacology of losulazine in the rat, cat, or a mixed anhydride. In method B, compound 3a was and dog has been reported.' Both animal pharmacology reacted with various reactive heterocyclic chlorides, acid and clinical experience suggest that losulazine hydrochlorides, isocyanates, and sulfonyl chlorides to produce chloride may be free of the clinically limiting side effects piperazines where the piperazine nitrogen is thus substiof most peripheral sympatholytics. tuted by the various heterocyles, carbonyl, carboxamido, Diverse biological activities have been reported for 4and sulfonyl groups that are shown in Table I. In method aminoquinolines. For example, chloroquine, hydroxyC, we first prepared the aniline side chain by the chemistry chloroquine, and amidoquine are well-known antimalarials that is depicted in Scheme I. The starting materials for that have 7-chloro-4-aminoquinolines as key structural these p-carboxamido, p-sulfonamido, and p-aminomethyl features." All of these antimalarials have a basic nitrogen anilines were prepared, respectively, from various secin a chain that extends from the 4-amino group. Rousondary amines and p-nitrobenzoyl chloride, p-nitrosel-UCLAF is developing two analgesic 4-aminoquinolines, benzenesulfonyl chloride, or p-nitrobenzyl chloride. The floctafenin and glafenine. Floctafenin bears an 8-trinitro groups of the products of these reactions were refluoromethyl group while glafenine has a 7-chloro quinoline duced catalytically or by titanium trichloride and the resubstituent. Both compounds have a 4-amino group that sulting substituted anilines were reacted with 7-(triis substituted by an aryl group."' In this respect, these fluoromethyl)-4-chloroquinolineto yield final products of two compounds are similar to the compounds of this paper, structures 3, 4, and 5 where W is carbonyl, sulfonyl, or although their biological activites are very different. methylene. In past work in our laboratories, 1-[4-[[7-(trifluoroPharmacology. The hypotensive activity, safety, and methyl)-4-quinolinyl]amino]benzoyl]piperazine (3aP was CNS side effect potential were evaluated for the 4identified during random screening as an interesting hyaminoquinolines that are described in this paper. Hypopotensive. This compound lowered blood pressure in rata tensive activity was assessed in the conscious rat. Drug but was associated with unacceptable toxicity in 90-day rat studies. Because of this, we sought a safer and more was administered orally at doses that ranged from 50 to efficacious analogue of 3a. This paper summarizes the 0.05 mg/kg. Blood pressure was measured at 0,4, and 24 search for such an analogue. Table I outlines the comh. Blood pressure effects are expressed as change in mean arterial pressure in mmHg relative to the predrug blood pounds that were prepared. Many of these are potent pressure. The results of these tests are summarized in Table I. Not all test drugs were screened for hypotensive activity at the same dose level and EDb0values were not (1) Wendling, M. G.;DuCharme, D. W.; Johnson, G. A.; McCall, R. B.; Pals, D. T. Fed. Proc., Fed. Am. SOC.Exp. Bid. 1983, obtained. Because of this, our structure-activity rela42, 162. tionship (SAR) conclusions are only rough. However, the (2) Surrey, A. R.; Hammer, H. F. J . Am. Chem. SOC.1946,68,113. apparent SAR is interesting. The hypotensive response (3) Surrey, A. R.; Hammer, H. F. J. Am. Chem. SOC.1950, 72, is maintained with wide variation in the side chains of the 1814. aminoquinoline. However, certain generalizations can be (4) Burckhalter, J. H.; Tendick, F. H.; Jones, E. M.; Holcomb, W. F.; Rawlins, A. L. J. Am. Chem. SOC.1948,70, 1363. made. In Table 11, the series is divided into three groups. (5) Anon., Belgian Patent 636381, 1964. Group 1shows the most dramatic potency and group 3 the (6) Allais; et al. Chim. Ther. 1973,8, 154. least. Usually, the benzamides (W = carbonyl, Scheme I) (7) Pottier, J.; et al. Eur. J. Drug Metab. Pharmacokinet. 1979, where the amine function is a piperazine or piperidine are 4, 109. superior to the analogous sulfonamides (W = SOz) while (8) Hsi, R. C. J. Labelled Compd. Radiopharm. 1976, 12, 601. the analogous benzylpiperazines are only minimally active. McCall, J. M. U.S.Patent 4167567,1979. The most active group of compounds consists of analogues (9) Horn, H. J. Biometrics 1956,12, 311. 0022-2623/86/1829-0133$01.50/0
0 1985 American Chemical Society
134 Journal of Medicinal Chemistry, 1986, Vol. 29, No. 1 Table I. Physical Data and Hypotensive Activity [ R compd 3a
NR2
CONR, (3),SO,NR, ( 4 ) , CH,NR, (5)]
formulau
mp,b "C
ref 8
A
N
=
McCall et al.
N-H
u
3b
213 decj
C27H22N40F4
c
3c 3d
"
2 ,H23N,F30
199-2Olj
method yield,d ABP, mmHg synth % [ 4 h/24 (dose)] e -15/-22 (50) -7/-8 (10) ia (3) c1 62 -11/-10 ( 5 ) - 1 2 / t 1 (1) A3 30 t 4/-13 (50)
277-278
B1"
22
210-2123'
A1
17
-lo/-16 ( 5 ) -7/-5 (0.5) -13/-27 (50)
3f
198-1995
A3
31
-19/-18 (50)
3g
251-252.5
B1
73
3h
271-27 2g
B1
35
-lo/-13 (5) t 2/-2 (0.5) -8/-16 ( 5 )
3i
283-2868
B1
80
-3/-4 (50)
260-2628
B1
43
-13/-29 (50) -lo/-24 (5) -2/-12 (0.5)
B1
61
-4/-3 (50)
215-217k
B4
95
-42/-25 ( 5 )
234-2368
B4
77
251-253g
B4
92
-2O/-34 ( 5 ) -13/-15 (0.5) -19/-25 (15) -17/-21 (1.5) -lo/-15 (0.5) -12/-14 (0.15) -6/-2 (0.05) -6/-3 ( 5 )
',HZ
3e
$F3N403S
26
3j
2 5 F3N4
O3
2 7 H 2 5 F3 N6 3'
3k
c2 7
31
1 '
3m
6HZ
>300k
1 ]F3N8
5 F3 N 4
so3
2 7HZ 2C1F3N,S03
3n
C26H22F4N4S03
30
2 S H 2 5 F3 N4S04
221-223g
B4
53
3P
2 3'
223-224.53'
B4
88
266-268g
B3
90
-la/-6 ( 5 ) -6/-2 (0.5) -14/-5 (50)
198-200
B3
68
-lo/-8 (50)
3q
2 4 F3N3
O3
C28H23C1F3N502
3r 3s
C29H26F3N502
3t
2 g H 2 1 F3N4
3'
280-282a
B3
93
-3/-9 (50)
268-26gm
B2
93
-11/-14 ( 5 ) -8/-4 (0.5)
B2
44
>280m
3u
0/-16 (5)
-l/+ 1 (0.5) 3v
232-235
A2
53
-4/-17 (50)
3w
245-247
A2
79
-19/-22 (0.5)
225-226
A1
57
250-251
A2
100
-7/-16 ( 5 ) -3/-11 (0.1) -15/-5 ( 5 )
237-238.5
A2
46
3x
C lN -
3Y N %
32
OCH, 2' 9
3 4F3N3
2
-6/-2 ( 5 )
Journal of Medicinal Chemistry, 1986, Vol. 29, No. 1 135
7-(Trifluoromethyl)-4-aminoquinolineHypotensiues Table I (Continued) compd
NR,
formulaa
3aa % N
Ca,Hz,F3N,Oz
C29H24F3N30
233-234.5
A2
30
-8/-8 ( 5 )
C,,H,,F,N,O,S
146-148f
c2
61
-1/-14
140-145f
C2
51
-lo/-13 ( 5 ) - 1 / O (0.5)
235-2373'
c3
86
-5/-16 (150) +1/-1(50)
H3
3bb N
,
M
u
C
H
'
u
4a
c 1, H, 5 F A 0 s*€3 2 2
~~~~
~
method yield,d ABP,mmHg synth % [ 4 h/24 (dose)Ie A2 92 -lo/-4 ( 5 ) -4/-1 (0.5)
mp,b "C 236-238
0
~
(5)
~~
Unless otherwise noted, all C, H, and N analyses are +0.4%. In degrees centigrade. See Scheme I. Percent yield of product-forming step, based on isolated pure product. e Average change in mean arterial blood pressure in mmHg a t 4 and 24 h after oral dosing of a conscious rat. Predrug pressure is 115-120 mm Hg. A change of 5 m m is significant (see Experimental Section). "ia" designates inactive. Data are presented in the form change a t 4 h/change a t 24 h (mg/kg dose tested). I n this model, Prazosin a standard compound, shows the following effects o n blood pressure: -26/+ 2 (1.5), -24/+ 3 (0.5), - 1 4 / t 1 (0.05). +From CH,Cl,/C,H,,. From CH,Cl,/CH,OH. From CH,Cl,. From CH,OH/EtOAc. From EtOAc. From CH,OH. From CH,Cl,/ether. From CH,OH/H,O. Calcd/found: C, 69.94/69.08; H, 4.65/ 5.19; N, 11.33/10.74. O Calcd/found: C, 66.78/66.26. Table 11. Hypotensive Structure-Activity Relationships
Table 111. Toxicity in Mice doselunacceptable clinical signsb*d 1000 >3160 >3160 >3160
clinical sign compda LD,n,b free doseb'c 3160 316 3d >3160 3160 100 100 3P >3160 I1 3a 1778 100 1000 1395
