J. Med. Chem. 1993,36, 2676-2688
2676
2-(Alkylamino)nicotinicAcid and Analogs. Potent Angiotensin I1 Antagonists' Martin Winn,' Biswanath De, Thomas M. Zydowsky, Robert J. Altenbach, Fatima Z. Basha, Steven A. Boyd, Michael E. Brune, Steven A. Buckner, DeAnne Crowell, Irene Drizin, Arthur A. Hancock, Hwan-Soo Jae, Jeffrey A. Kester, Jang Y. Lee, Robert A. Mantei, Kennan C. Marsh, Eugene I. Novosad, Karen W. Oheim, Saul H. Rosenberg, Kazumi Shiosaki, Bryan K. Sorensen, Ken Spina, Gerard M. Sullivan, Andrew S. Tasker, Thomas W. von Geldern, Robert B. Warner, Terry J. Opgenorth, Daniel J. Kerkman, and John F. DeBernardis Abbott Laboratories, Cardiovascular Research Division, Pharmaceutical Products Division, Abbott Park, Illinois 60064 Received February 25, 1993
A series of pyridines and other six-membered ring heterocycles connected to a biphenylyltetrazole with a-CHrNR'-link (1) were discovered to be potent angiotensin I1antagonists. In the pyrimidine carboxylic acid series (W= CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were much more potent than compounds with an alkyl group (R) on the heterocyclic ring. The corresponding pyridine, pyridazine, pyrazine, and 1,2,4-triazine carboxylic acids also showed potent in vitro angiotensin I1 antagonism. The pyridine (W, X, Y = CH, Z = COOH, R' = n-CsH7) demonstrated potent in vitro activity (pA2 = 10.10, rabbit aorta, and Ki = 0.61 nM, receptor binding in rat liver) as well as exceptional oral antihypertensive activity and bioavailability. Any nonacidic replacement for the carboxylic acid waa detrimental for activity. The renin-angiotensin system (RAS) is known to play an important role in cardiovascular regulation. On the basis of the success of the angiotensin-convertingenzyme inhibitors as antihypertensive drugs,there has been intenae effort in the pharmaceutical industry to discover renin inhibitors and angiotensin I1 (A-11) antagonists as alternative means of inhibiting the RAS. The developmentof nonpeptide A-I1 antagonists was initiated by Takeda chemists, who reported on imidazoles such as 2a, which possessed weak activitye2DuPont scientists subsequently discovered the importance of linking the imidazole to a biphenylyltetrazole moiety, leading to the discovery of the orally active DUP-753 (Losartan 2b),3 which is in clinical trials.
2d. R = C~FS. X = COOH.Ar BPT I
"I
4
CH,BPT
'3
5
AH,BPT
~CH,BPT
Figure 1. Since then, there have been many other reports of A-I1 antagonists that contain an alkyl-substituted nitrogen heterocycle connected to a biphenylyltetrazole by a methylene or an ether link. Examples of these heterocycles include imidazo[4,5-blpyridine (3): pyrazolo[l,5-alpyrimidine (4),5 pyrazole (5),Z7 quinoline (6),8 1,5-naphthyridine (7): and triazolones (@.lo At the start of our work, only the imidazole-containing A-I1 antagonists 2a-d were known. We chose to examine Addrese correspondenceto Abbott Laboratories, Dept 47V,AP-10, One Abbott Park Road, Abbott Park, Illinoia 60064. 0022-262319311836-2676$04.00/0
Scheme I NaN3
-
TrBPT CHz Br
-- TrBPT - CH2N3 11
10
LiAIHI
/TrBPT
- CH2NH2
13
R"H2
-
TrBPT CHzNHR'
12
related compounds based on six membered ring heterocycles. From the published structures, it appeared that a target compound should incorporate a carboxylic acid, an alkyl group, and a tetrazole-substituted biphenyl moiety, each attached to the central heterocycle. What remained to be determined, however, was the exact placement of these groups on a six membered ring, and the optimum choice for the heterocycle itself. Heterocycles that incorporated a number of these features, suchas pyrimidines 911(Scheme 1I) and pyridines 29 (Scheme VI), were readily synthesized. Furthermore, they contained a reactive chlorine through which the biphenylyltetrazole group could be easily attached via a heteroatom linkage. A nitrogen was chosen for this purpose since an amine was sufficiently reactive to add to the activated heterocycles and the nitrogen would also provide a region for additional structure exploration. Chemistry The chloropyrimidines 9ll were directly coupled (see Scheme 11) with amino derivatives of the biphenylyltetrazole (12 and 13). These were prepared from the known (bromomethyl)biphenylyltetrazolelz(see Scheme I). The trityl-protected compounds (14) were deprotected under acidic conditione to give the esters, which were then hydrolyzed with base to the carboxylic acids 16. Alcohols 17 were obtained by reduction of 14 with L A H , followed by detritylation with acid. When R = CHsOCHzCHz, 9 could not be prepared from the corresponding hydroxyl compound without cleavingthe ether. Instead the product Q 1993 American Chemical Society
2-(Alkylamino)nicotinic Acid and Analogs
Journal of Medicinal Chemistry, 1993, Vol. 36, No. 18 2677
Scheme VI
-
29, W - Me, El
10
COOR'
R"H2
' - ~ N H R
LlN(TMS)p
-
RiT;:
30
31
I
Q I N(R')-CHp-BPT
1) HCOOH 2)NaOH
QTr I N(R')- CHz- BPT-Tr
__
17
-
32 (X C O W )
'mCl -
1) M M C l
NaSMe
CmEt
RaNi
29 (R =5-F)
MaS MeS
34
35 5 "0,
O I N a C m H
-
1)soc12
29 (R 5-NO2) a
O
H
OH
36
Scheme I11
2) EtOH
37
I
1) MeOH, H S 0 4 2) N-iodosuccinimide
18
38
19
Scheme IV c I n c M ) E t
12
~
20
36
1)HCOOH
CI
ET3N
N
QTr
2)NaOH
21
-
1) CBH5CH20Na
CyI+O f OH
2) H2. 3) NaOH
F
N
Q
23
-
1) soc12 2)MeOH
OH
ay c'ncmE1 ___)
N
-"a
29 (R I 561)
32X (R = &OH, X = COOH)
39
1) H2,2) HCOOH, 3) NaOH
31 (R-5-NO2)
Hz
31 (R-5-NH2)
AczO
31 (R-5-NHAC)
Scheme VI1 24
LIAIH,
31
Scheme V
HCOOH a : T r
a:
-
59, X-CH20H
26
25
I
OH
27
1) HCOOH, 2) NaOH
MeMgBr
ll)EF\
59, XI AHCH,
1
MnO2
-
60, X = CH20H
HCOOH
59, X CHO
60.X = CHO OH I
2) HCOOH
59, X CHCH2COOEt . I
1
R
28
was made by way of the methanesulfonate intermediate (see Scheme 11). Similarly, 1,2,4-triazines,pyrazines, and pyridazines were prepared from esters 18, 21, and 25, respectively, using halogen or benzenesulfonate leaving groups (see Schemes 111-V). The chloronicotinates 29 (R = H, Me, and C1) did not react with the secondary amine 12. Therefore these pyridines were constructed in two steps (Scheme VI). Reaction of primaryamineswith 29 yielded 24alkylamino)nicotinates 30, which were alkylated with bromide 10 to give the protected compounds 31. When R = 6-F, 5-F, or 5-1, the 2-chloro group in 29 could be directly displaced with the secondary amine 12, Ethyl 2,6-difluoronicotinatal4reacted with 12 in the desired 2-position,based on the diagnostic splitting observed between the 6-F and 5-H in the 'H NMR spectrum. The &fluor0 compound was prepared from the known15compound 34, by displacement with methyl mercaptan in the 6-position (structure de-
60, X-ECH,
1) NaOH 2) SOCl2
31 3) CsH5=~"2 4) HCOOH
60, X-LHCH,
-
60, x 0
-
1) HCOOH 2) NaOH
OH LHCH2COOH
II
60, X = CNHSOZC~H~
termination by X-ray) and subsequent desulfurization of 35 with Raney nickel to give 29 (R = 5-F). The other substituents (Cl,I, NO2) at the 5-position of the nicotinic acid were introduced by way of electrophilic substitution on 36 (see scheme VI). The 5-phenyl analog was conveniently made by a palladium-catalyzed coupling reaction of the 5-iOdO ester 31 with phenyl boronic acid. The 6-hydroxy compound was prepared from the 6-fluor0 compound as shown. The 5-carbethoxy group in 31 was converted to CH2OH, CHO, CH(OH)Me,CH(OH)CH2COOH,COCHs, and CONHSO2C6H5groups as outlined in Scheme VII. The starting material for the synthesis of the 3-CN, CONH2, and CHzNHS02CF3 analogs was 2-chloronicotinitrile
Winn et al.
2678 Journal of Medicinal Chemistry, 1993, Vol. 36, No. 18
Scheme XI
Scheme VI11 COOMe
12, EbN
cI
120', 6 hr
COOMe ' a 0 T r
40
1) HCOOH
COOH
2)NaOH
a
41
64
63
42
32mm, X OCONHCH3 . I
-
32pp, XI OCOCHJ
Scheme XI1 CH3
49
65
64
51
1
1) HCOOH 2) NaOH
"r', 52
1)HCOOH 2) 10, LiN(TMS)z
COOH
2) NaOH
56
a
57
58
Scheme IX
J
1
LiAHI
59, X-CHflHz
Scheme XI11
71, R - M e NaOH
32Y (X
CONHJ
. I
ycbs
Scheme X
2) T ~ O T I
COOR
1
-
59, X-NOz
-
32rr,32ss X
NHS02R.
-
I
t
1) R'SOzCIor
(R'SOdzO 2) HCOOH
HZ
59, X NHz I
3222. (X Nod
1) CHsNCO
1) R'COCI or (R'CO)*O 2) HCOOH
-
3 2 X~ NHCSNHz
32~U 3hrV 32n
NaOH ,or R. cOOEt I
1
1) TBAF 2) NaOH
76 (75, R
32XX, XI NHCONHCHJ
2) HCOOH
/I
-
Pr
75. R -Me, R' SiMeztBU
32ww X .INHCOCWH
XI NHCOR'
(Scheme IX). 3-'Nitro-2-chloropyridinereacted with 12 to yield the nitro compound 59, which was converted into a wide variety of 3 nitrogen-substituted nicotinic acid analogs as shown in Scheme X. Commercially available 2-amino-3-(benzyloxy)pyridine(63) was transformed into several 3-oxygen-substitutedanalogs as shown in Scheme XI.
3)NBS 4) 30,LiN(TMS)Z
74
-
R' H)
I
All of the above compounds possessed a common alkylamino linking group which was flanked on one side by a cwboxyl or other polar group, and on the other aide by a ring nitrogen. To study the effect of varying the position of the ring nitrogen and carboxylic acid relative to the linkinggroup, other pyridines and pyrimidines were synthesized (Scheme VIII). The methods used were as follows: (1)direct secondaryamine 12 displacement of a halo heterocycle (i.e. 40 and 53); (2)sequential displacement and alkylation (i.e. 43 and 49); and (3) double alkylation of a heterocyclic primary amine (46 and 56). The simple methyl and unsubstituted pyrimidine analogs were synthesized from the known starting materials 64, 66, and 68 (Scheme XII).
2- (A1kylamino)nicotinic Acid and Analogs
Journal of Medicinal Chemistry, 1993, Vol. 36, No. 18 2679
Table I. Pyrmidine, Pyrazine, Pyridazine, and Triazine Carboxylic Acids COOH
R
R'
rnD* formulac -DAP _ (OC) . _ 5.61 (0.08) 2 a 7.50 (0.11) 2 211-212 8.30 (0.04) 2 200-202 223-225 8.27 (0.37) 2 7.91 (0.23) F 193-195 7.23 (0.07) 2 166-168 6.81 (0.01) 2 235 7.15 (0.02) 2 166169 a 7.96 (0.02) 2 a c9H7 9.60 (0.19) F 155-158 cae 8.81 (0.16) F# a call 8.73 (0.05) 2 CHzCH=CHz 8.32 (0.14) F a CH&HMez 7.60 (0.04) 2 a a (CHz)zCHM% 8.85 (0.03) 2 CH&HzOCHs 8.50 (0.01) 2 a a CsHi 9.68 (0.09( F a cas 9.57 (0.16) F a c B H 7 8.52 (0.04) 2 a CsH7 8.79 (0.09) 2 a cas 8.38 (0.11) 2 a cas 7.95 (0.06) 2 a cae 8.48 (0.04) 2 a CSH? 8.00 (0.07) F c&, 8.90 (0.03) 3 102-104 CHB H cae 9.70 (0.10) 6 a CzsH~N70z C8H7 8.31 (0.08) 2 a CaH&lN7Or0.25i-PrOH c1 c1 cae 9.04 (0.12) 2 a C&aClN,02.0.25i-PrOH CaHi 9.69 (0.20) 6 a CaH~1N70r0.25i-PrOH H H cas 10.25 (0.15) 4 a C&~70z*0.5Hz0 3A2 in rabbit aorta (standard error), no. of determinations for estimated PAS, or F for full pA2. Slope for full pA2 is between 0.95 and 1.151unleeeotherwise noted. See ExperimentalSection. * "a" denotes amorphous or no attempt waa made to crystallizethe compound. Analysis for cI, H, and N are within &0.4%of theory. Nitrogen low by 0.4 to 1.0%.* C: calcd, 59.29; found, 60.07. f H calcd, 5.15; found, 5.68.8 Slope = 1.21.
no.
16a 16b 16c 16d 16e 16f 16g 16h 16i 16j 16k 161 16m 16n 160 16p 16q 16r 16s 16t 16u 616 612 210 218a 218b 213a 213b 214a 214b
H
H H H H H H H CHs CaHs
The benzoic and salicylic acid analogs of the phenylteb razole were synthesized as outlined in Scheme XIII. Starting material 7012 was used in place of 10 to prepare the carboxylic acid 71. The salicylic acid was synthesized by a palladium coupling of triflate 73 with tolyl boronic acid to give biphenyl 74 which was ultimately converted to the desired compound 76.
Biology Antagonism of Angiotensin I1 in the Rabbit Aorta. The compounds were evaluated for their potency in antagonizing the ability of angiotensin I1 to contract the rabbit aorta. Potencies were calculated as pA2 values, the definition of which is as follows. If at drug concentration of 10-s molar in the bath, one must double the concentration of angiotensin I1to get the sameeffect on the rabbit aorta that one gets without the drug, then the pA2 is x . The higher the pA2 value, the more potent the drug. The standard error in the pA2 determination varies, but we would consider a pA2 difference of 0.25 between two compounds to be meaningful. See the Experimental Section for the difference between a full and estimated pA2, and for the definition of the slope. Our first series of compounds were the CHzNH linked 2-alkyl pyrimidine carboxylic acids (Table I, compounds 16a-g). The 2-ethyl and 2-propyl compounds had pA2 values of 8.27 and 8.30, respectively, in the rabbit aorta, and thus were comparable in vitro to DUP-753. Shorter
or longer alkyl groups weakened activity. The corresponding esters and alcohols (Table 11)were roughly 3-fold weaker. Conversion of the secondaryamine in the linking group to a tertiary amine improved in vitro potency. Highly potent A-I1 antagonists were achieved with the n-propyl 16qand n-butyl16r derivatives. The optimal substituent in the 2-position was hydrogen. Pyrimidine isomers (62 and 65) were much less potent. The methyltriazine 20 was less active than the corresponding pyrimidine 16j, while the pyrazine 28b and pyridazine 24b were equal or slightly more active than the corresponding pyrimidine 16k. A chlorine on the pyridazine ring (23) reduced potency. Removing one of the nitrogens in the pyrimidine ring resulted in the pyridine series which proved to be 5-fold more potent (compare32c, Table I11to 16q, Table I).The optimal substituent on the exocyclic nitrogen was either n-propyl or n-butyl. Any substitution on the pyridine ring (Table IV) reduced the activity;the most detrimental being 6-Me0 or 6-OH; the least detrimental being 4-CH3, 5- or 6-F, and 5-C1. The 5-position could tolerate a degree of bulk, e.g. phenyl, but polar groups, e.g. AcNH or NH2 were not accommodated. Compound 32f with a pA2 of 10.33 and 32c (A-81988)with a pA2 of 10.10 are among the best angiotensin I1antagonistsdescribed to date (seeTable VII). A-81988, 16q, and 16r showed competitive antagonism (slopes = 1.06-1.09) whereas L158809 (3, slope = 1.37),DUP-532 (2d, slope = 1.811, EXP-3174 (2c,slope =
2680 Journal of Medicinal Chemistry, 1993, Vol. 36,No.18 Table 11. SAR of 2-Alkylpyrimidines-Noncarboxylic Acids
Winn et al. Table IV. 2-(Alkylamino)nicotinic Acids-SAR on the Pyridine Ring
of Substituents
COOH R
R i 9 N - R
y-Pr
6 7 CHZBPT
R
no.
1Sa 1Sb 150 1Sd 16e 1Sf 1Sg 17b
H CHs CzH6 CsH7 C~HS
X
pA2a
COOEt COOEt COOEt COOEt COOEt call COOEt CHaOCHzCHz COOEt CHS CH2OH
6.24 (0.08) 2
mpb ( O C ) a 121-123 114-116 132-133 145-146 131-133
69
formulae
7.13 (0.07) 2 7.78 (0.05) 4 7.91 (0.02) 2 7.37 (0.02) 2 6.37 (0.32) 2 7.10 (0.03) 2 122-124 7.12 (0.06) 2 199-201
170 C2Hb
CHzOH 7.96 (0.02) 2 217-219
17d CaH,
CHzOH 7.60 (0.44) F 214-216
17e ClHs
CH2OH 7.53 (0.21) F 152-159
17g CHaOCHzCHz CHzOH 6.41 (0.11)2 218-220 65
7.90 (0.06)3
67
7.65 (0.10) F 148-150 8.08 (0.02) 2 a
69 a-d
a
See Table I.
32
CHPT
no. 32c 32j 32k 321 32m
R H 4-CHa 5-CH3 5-C1 5-F
~H,BPT
R' PAZ' CsH7 10.10 (0.08) Ff CSH7 9.64 (0.02) 2 C3H7 8.80 (0.09) 2 C3H7 9.07 (0.04)2 C3H7 9.04 (0.02) 2
formula CzaHnN&zd
CUHuN6Ozd CUH~NSOZ~ CmHziCMeOz CgHzlFN& 0.6CFsCOOH 3211 5-1 CiHa 8.38 (0.15) F CaJIJNuOr . . __ O.CSF~COOH C3H7 8.91 (0.20) 2 C&zsNeOr1.5H20. 32p 5-C& CsH7 8.33 (0.03) 2 CzaHz1N~0~~1.5HzO 32s 5-NOs C&, 32; 5-NHi 7.60 (0.03) 2 C&€&O;d 326 5-NHCOCH3 CsH7 7.90 (0.02) 2 C&&Os*1.33Hz0 32t 6-CH3 C4H9 8.15 (0.07) 2 ClaHaSNeOz 3 2 ~6-F C3H7 9.63 (0.30) 2 CaaHziFNsOr 0.75CFsCOOH 32w 6-CHsO C3H7 7.78 (0.02) 3 CUHpcN6O8* 0.9CFsCOOH 32s 6-OH CaH7
