J . Med. Chem. 1989,32, 1552-1558
1552
2( 1H)-Quinolinoneswith Cardiac Stimulant Activity. 3. Synthesis and Biological
Properties of 6-Imidazol-1-yl Derivatives Andrew S. Bell, Simon F. Campbell,* David S. Morris, David A. Roberts, and Mark H. Stefaniak Department of Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, United Kingdom. Received August 29, 1988 A series of 6-imidazol-l-yl-8-methyl-2( 1H)-quinolinoneswas synthesized and evaluated for cardiac stimulant activity in dogs. The majority of compounds were prepared from an appropriate 6-imidazol-l-yl-2(1H)-quinolinoneprecursor Introduction of a range or by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide. 1H)-quinolinone (1) reduced inotropic activity in of 5-substituents into 6-(2,4-dimethylimidazol-l-yl)-8-methyl-2( anesthetized dogs (percentage increase in dP/dt,,) although replacement of the 2-methyl group by iodo (10) or cyano (11) substituents was well tolerated. The 2-methyl-4-chloro(15) and 2-methyl-4-(methylthio)(22) derivatives displayed similar potency to 1 (40-50% increase in dP/dt,,, 10-12.5 fig/kg) and these compounds were 3-5 times more potent than milrinone. Introduction of iodo (14), cyano (16), or acetyl (17) substituents into the 4-position approximately halved inotropic activity. In conscious dogs, 11 (0.25 mg/kg) and 16 and 17 (0.125 mg/kg) produced similar increases in cardiac contractility (decrease in the QA interval) to 1 (0.125mg/kg) and maximum responses were maintained for at least 3 h. Dose-related (25, 125, 250 fig/kg) cardiac stimulant activity was demonstrated by 17 and after the higher doses a marked response (approximately 30% increase in dP/dt,,) was still observed after 7 h, in contrast to milrinone. The substantial increases in cardiac contractility observed with 16 and 17 in the conscious dog were not accompanied by any tachycardia. These compounds also displayed an overwhelming selectivity for increasing the force of cardiac contraction (>120% increase in dP/dt,,) rather than heart rate (5-10 beats/min decrease) in the Starling heart-lung preparation. As a result of this beneficial pharmacological profile, 6-(4-acetyl-2-methylimidazol-l-yl)-8-methyl-2(lH)-qu~olinone (17, UK-66,838)was selected for preclinical development studies.
Chemistry Table I lists all of the novel 2(1H)-quinolinones (2-24) which were evaluated for cardiac stimulant activity, and synthetic routes A-L are summarized in Schemes I and 11. Apart from 8, 12, and 14, which were prepared by sulfuric acid catalyzed cyclization of an N-(6heteroarylphenyl)-3-ethoxypropenamide(25-27,route G2),all of the compounds in Table I were synthesized from an appropriate 6-imidazol-l-yl-8-methyl-2(l~-quinolinone precursor. Thus, electrophilic halogenation of 1 with Nchloro- or N-bromosuccinimide (routes A and B) or iodine N*CH3 monochloride (route C) gave the 5-halogeno derivatives (2-4). Treatment of 6-(4-methylimidazol-l-yl)-8-methylX(1H)-quinolinone (28) with 2 equiv of n-butyllithium followed by iodine provided a regioselective entry to 10 CH3 (route I). The above iodoquinolinones (4,10,and 14)also CH3 1 served as versatile intermediates for the introduction of a range of alternative substituents into the imidazolyl ring velopment,4* and phase I1 evaluation in congestive heart system (Scheme 11). Thus, treatment of 4 and 14 with failure patients is in progress. This compound was some sodium thiomethoxide in the presence of copper(1) chloride 5 times more potent than milrinone as an inotropic agent as catalyst gave 5 and 22,respectively (route D), which in and also displayed a more prolonged duration of action turn allowed access to the corresponding sulfoxides (6and after oral administration to conscious dog^.^,^ In order to 23) and sulfones (7 and 24) following S-oxidation with extend these observations, a wider range of substituents m-chloroperbenzoic acid (routes E and F). Treatment of has been introduced into the imidazolyl ring system in 14 with copper(1) chloride provided 15 (route H) while and SARs for inotropic activity have been determined. As reaction of 4, 10, or 14 with copper(1) cyanide in the a consequence, 6-(4-acetyl-2-methylimidazol-l-yl)-8presence of palladium acetate as catalyst' at 175 O C gave methyl-2(lw-quinolinone (17,UK-66,838) was identified 9,11, and 16 (route J). Compound 16 was subsequently with a similar overall pharmacological profile to 1 and was converted to the ketone derivatives (17-20)on treatment selected for preclinical development studies. with an appropriate Grignard reagent (route K). Finally, a palladium-catalyzed cross-coupling reaction8 between 10 or 14 and phenylzinc chloride gave 13 and 21,respectively Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.; Henderson, C. G.; Roberts, D. A.; Ruddock, K. s.;Samuels, G. M. (route L). R.; Stefaniak, M. H. J . Med. Chem. 1988, 31, 1031. Syntheses of the intermediates (Table 11) required for Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.; Henthe preparation of the propenamides (25-27) used for route derson, C. G.; Morris, D. s.;Roberts, D. A.; Ruddock, K. s.; G are summarized in Scheme 111. Thus, reaction of 5Samuels, G. M. R.; Stefaniak, M. H. J . Med. Chem. 1989,32, fluoro-2-nitrotoluene (29)with an appropriately substi575. tuted imidazole (39-41)in dimethylformamide a t 120 "C Ellis, P.; Henderson, C. G.; Samuels, G. M. R. Br. J . Pharmacol. 1987, 91, 392P. Alabaster,C. T.; Rance, D. J. Br. J. Pharmacol. 1987,91,39lP. Campbell, S. F.; Roberts, D. A. European Patent 0226357, (7) Takagi, K.; Okamaoto, T.; Sakakibara, Y.; Ohno, A.; Oka, S.; Hayamu, N. Bull. Chem. SOC.Jpn. 1975,48, 3298. 1987. Campbell, S. F.; Morris, D. S.; Roberts, D. A. European Patent (8) Negishi, E.; Luo, F.-T.; Frisbee, R.; Matsushita, H. Heterocy-
Previously, the synthesis and inodilator properties of a series of 2( 1H)-quinolinone derivatives incorporating a variety of six- and five-membered heterocyclic moieties were These studies confirmed that location of the heteroaryl function a t the quinolinone 6-position was preferred and that an 8-methyl substituent improved both inotropic potency and duration of action. As a result of these initial structure-activity relationship (SAR) studies, 6-(2,4-dimethylimidazol-l-yl)-8-methyl-2(1H)quinolinone (1,UK-61,260) was selected for clinical de-
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0022-2623/89/1832-1552$01.50/0 0 1989 American Chemical Society
Journal of Medicinal Chemistry, 1989, Vol. 32, No. 7 1553
2(1H)-Quinolinones with Cardiac Stimulant Activity
Table I. Synthetic Routes and Physicochemical Data for Imidazolylquinolinone Derivatives NdR2
hANqQo H
CH3
no.
R4
R2
R5
c1
CH3 CH3 Br CH3 CH3 I CH3 CH3 SCH, CH3 CH3 SOCHa CH3 CH3 S02CH3 CH3 CH3 COCH3 CH3 CH3 CN CH3 CH3 H I CH3 H CN CH3 COCH:, CH3 H H CBH5 CH3 I H CH3 c1 H CH3 CN H CH3 CH3 COCHB H COC2H5 H CH3 CO-i-CaHT H CH3 COC6H5 H CH3 C6H5 H CH3 SCH3 H CH3 SOCH, H CH3 SOpCHa H CH3 "N:calcd, 14.6; found, 14.1. *N: calcd, 14.2; found, 13.7. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
route A B C D E F G J I J G L G H
J K K K K L D E F
mp, "C 265-268 273 242-245 263-265 283-285 276-278 240-242 334-337 260 302-304 312-314 293-295 285-287 347-350 >350 306-308 261-263 224-227 290-293 280-282 255 292 332-333
formula C15H14C1N30 C15H14BrN30
C15Hl4IN30*0.5H20 Cl6H17N302S.0.33H20 C16H17N303S
C17H17N302 C16H14N40.0.25H2O C14H12IN30.0.66H20 C16H12N40
C16H15N302.0.25H20 CzoH17N30.0.5HzO C14H121N30 C14H12C1N30
C15H12N40.0.67H20 Ci6H15N302*0,17H20 C17H17N302
Cl~Hl~N302.0.17HzO C21H17N302.0.5H20 CmH17N30.0.33HzO C1SH15N309.0.5HzO C15H15N302S*1.25H20 C15H1SN303S
anal. C, H, N" C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, Nb C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N
Scheme I
Scheme I1 CN
' H CH3 9,11,16
I
0
17
- 20
gave 30-32 with greater than 95 % regio~electivity.~Reduction with stannous chloride then provided the anilino derivatives (33-35). Surprisingly, selective iodination of the imidazole ring in 34 was achieved with iodinefsilver sulfatefsulfuric acid whereas reaction with bromine in acetic acid occurs ortho to the amino function.2 Presumably, in the former case both the amino and imidazolyl (9) Imbach, J.-L.; Jacquier, R. C. R. Seances Acad. Sci., Ser. 2 1963,257, 2683.
13,15,21
6,7,23,24
systems are fully protonated and, consequently, the aromatic ring is more severely deactivated. The iodinated product 1-(4-amino-3-methylpheny1)-5-iodo-2,4-dimethylimidazole (36) allowed access to the corresponding 5-cyano (37) and 5-acetyl (38) derivatives by the methods of routes H and L. Finally, treatment of 33, 35, and 38 with trans-3-ethoxypropenoyl chloride provided 25-27. The imidazole derivatives (39 and 40) required for reaction with 29 were prepared from 2- and 4-methylimidazole (42 and 43), respectively. Thus, treament of 42
Bell et al.
1554 Journal of Medicinal Chemistry, 1989, Vol. 32, No. 7 Table 11. Synthetic Routes and Physicochemical Data for 1-(3-Methylphenyl)imidazole Derivatives
C"3 no.
X
R'
R4
R5
mp, OC
formula
anal.
NHCOCHCHOCzH6 CH3 I H 172-174 C16H181N30P NHCOCHCHOC2H6 COCH3 CH3 H 189-1 91 C18HZ1N303 NHCOCHCHOCzH, CH3 CH3 COCH, oil" I H 146-148 CllH101N302 NO2 CH3 CH3 H 135-138 C12H13N302 NO' CH3 157-159 C13H13N303 NO2 COCH3 CH3 H NH2 CH3 I H crude" 342 NH2 CH3 CH, H 118-1 20 C12H15N3 COCH, CH3 H 157-159 C13H16N30.0.17HzO 35 NH2 I crude" CH3 36 NHZ CH3 CH3 CN 152-154 C13H14N4.0.33HzO 37 NH2 CH3 38 NH2 CH3 CH, COCH, oil" " Characterized spectroscopically. *C: calcd, 60.2; found, 59.7. C: calcd, 71.6; found, 71.0. 25 26 27 30 31' 32 33
C, H, N C, H, N C, H, N C, H, N C,* H, N C,' H, N C, H, N C, H, N
Scheme 111"
b
NO2
30
-
32
NH2
CH3
33
la
R 4 9 - @ I
dC, e
R4$
