J. Med. Chem. 1980,23, 1445-1448
1445
point and to extend the structure-activity correlation. 2-Substituted compounds are generally somewhat more active than 3-substituted compounds2Jr8and consistent with this the 3-cyano derivative (IV)is less active than the 2-nitro derivative (111). Because of the limited number of structures determined and the presumed importance of electronic, hydrophobic, and other physical chemical factors, any correlation between biological activity and solid-state structure can be, at best, of limited scope. However, there is some indication that activity does vary according to the planarity of the 1,4-dihydropyridine ring, as measured by torsion angles about C4 (Table VIII), activity increasing with increasing ring planarity.
Table VIII. Inhibition of Muscarinic Responses of Guinea Pig Ileal Longitudinal Smooth Muscle by 1,4-Dihydropyridines torsion act. (III angle,b no. ID.,. Ma = 1.01 deg I 9.0 X lo-'" 6.0 16 I1 5.0 X lo-' 0.0001 28 I11 (nifedipine) 5.1 X 1.0 20 IV 3.0 x lo-' 0.017 30 Measured against tonic (slow) response to the muscarinic agonist, cis-2-methyl-4-[(dimethylamino)methyl] 1,3-dioxolane methiodide (CD), according to our previously described method.' Average of the two torsion angles (C,-C,-C,-C,, C,-C,-C,-C,, Table VI) describing the distortion from planarity of C, of the 1,4-dihydropyridine ring.
Acknowledgment. This work was supported by NIH Grants HL 16003 and RO 545417. We appreciate the continued interest and support of our colleagues A. B. Triggle, J. A. Triggle, D. B. Shefter, and D. M. Shefter.
pig ileal longitudinal smooth muscle?l2 are given in Table VIII. The order of activity, I > I11 > IV > 11, demonstrates, as noted p r e v i ~ u s l y , ~the ~ ~highly ~ * detrimental effects of 4-substitution in the phenyl ring. The high activity of the pentafluoro derivative (I),which contains a 4-F substituent, may be due to the activity-enhancing effects of the two ortho and two meta substituents, which are sufficient to overcome any detrimental effects of 4substitution. Structural studies are continuing to test this
Supplementary Material Available: Crystallographic data for molecules I-IV (Table I); fractional atomic coordinates for I with estimated standard deviations X104 (Table 11); fractional atomic coordinates and estimated standard deviations X104 for compounds 11-IV (Table 111); bond distances (A) for compounds I-IV (Table IV);bond angles (degrees) for compounds I-IV (Table V); torsion angles for compounds I-V (Table VI); and intermolecular hydrogen bond data for compounds I-IV (Table VII) (7 pages). Ordering information is given on any current masthead page.
(12) L. B. Rosenberger, M. K. Ticku, and D. J. Triggle, Can. J. Physiol. Pharmacol., 57, 333 (1979).
Lipophilic and Hydrophilic Esters of 4-Acetyl-2-(2-hydroxyethyl)-5,6-bis(4-chlorophenyl)-2H-pyridazin-3-one as Antihypertensive Agents S. W. Fogt, J. A. Scozzie, R. D. Heilman, and L. J. Powers* Diamond Shamrock Corporation,
T.R. Evans Research Center, Painesville, Ohio 44077. Received December 17,1979
In an attempt to enhance the antihypertensive activity of 4-acetyl-2-(2-hydroxyethyl)-5,6-bis(4-chlorophenyl)-2Hpyridazin-3-one, 1, a series of lipophilic and hydrophilic eaters was synthesized. These derivatives possessed increased lipid and aqueous solubility, respectively. The esters, in general, cause a larger blood-pressure drop than 1 when tested at high doses in the spontaneously hypertensive rat (SHR) model. At lower doses the antihypertensive activity is the same as with 1.
hypertension. Evaluation of this compound established As described in the accompanying paper,' 4-acetyl-2(2-hydroxyethyl)-5,6-bis(4-chlorophenyl)-2H-pyridazin-3- that, while a statistically significant reduction in blood pressure does occur following a dose of 3 mg/kg in these one (1) is active in the spontaneously hypertensive rat models, reduction of blood pressure to less than approximately 140 mmHg does not occur even at doses of 100 mg/kg. Indeed, a plot of the dose-response relationship for this compound plateaus at less than 50 mg/ kg. It was also observed that 1 has limited solubility in both water and lipophilic solvents. In order to determine if the efficacy of this compound could be improved, a series of esters of the 2-hydroxy function was synthesized. The initial series which we will describe is a series of alkyl and CI aryl esters which were designed to have higher solubility in lipid solvents. The second series that we will discuss 1,R=H 2, R = COCH, are amino acid esters of 1 with increased water solubility. The synthesis of amino acid derivatives as potential pro(SHR) and the deoxycorticosteroid (DOCA) rat models of drugs has been reported p r e v i o u ~ l y . ~ ~ ~ (1) R. Buchman, J. A. Scozzie, Z. S. Ariyan, R. D. Heilman, D. J. Rippin, L. J. Powers, and R. J. Matthews, J. Med. Chem.,
under articles section in this issue. 0022-2623/80/ 1823-1445$01.00/0
(2) I. M. Kovach, I. H. Pitman, and T. Higuchi, J.Pharm. Sci., 64,
1070 (1975). 0 1980 American Chemical Society
1446 Journal of Medicinal Chemistry, 1980, Vol. 23, No. 12
Notes
Table I. Esters of 2-(2-Hydroxyethy1)pyridazinones
1
CI
no.
R
mp, "C
synth solvent
% yield method
99-102 45-49 82-86
Ch,C,H, CH,NH-C bz CH(NH-Cbz)C(CH,),NHC(")"NO, CH(NH-Cbz)CH,C,H, 11 (CH,),NH-Cbz 12 CH( NH-Cbz)CH( CH, ), 13 CH.NH-t-Boc 14 CH(+NH,Br')( CH,),NH,'Br15 CH,NH,' Br16 CH-NH.+C117 CH(+N~,CI-)(CH,),NH,+C~18 CH(+NH,Cl-)CH,C,H, 19 CH(+NH,CI-)CH(CH,), 20 (CH,),NH,'Cl21 CH('NH,Cl- )(CH,),SCH, 22 a s = softens. FD = freeze-dried. Anal. 8 9 10
43-46 98-100 134-135 84.5-86 85-87
63 49 48 31 24 45 40 69 21
CH,Cl,-C,H,, MeCN
A A A
A
A A A C B
formula 1ZH
1 8C1,N,04
C2SH24C12N204
C23H20C12N204
c 24H z N c404 c 27H2 oCIJ,O4 2
2
C38HS0C12N204
C28H22C12N204
c
3 O H 2 Scl 34
2
1
H 3 3 C1,N 7 0
6
8
59-60 42 33 49-52 112-11 3 MeCN-Et,O 36 54 60-63 F D ~ 125 sa 110 sa FD 127-130 FD 66 140-144 FD 40 52 123-126 FD 124-128 31 FD 138-140 FD 75 102-105 FD 43 H : calcd, 5.1;found, 4.5. C1: calcd, 19.1;found, 19.0
Chemistry. The aliphatic and aromatic esters were synthesized from 1 and the appropriate acid chloride (Table I). Amino acid esters were obtained by coupling a protected amino acid and 1 using standard methods of peptide synthesis. Dicyclohexylcarbodiimide (DCC)4or the mixed anhydride method5 using isobutyl chloroformate or pivaloyl chloride was employed. The Cbz groups in N-(carbobenzyloxy)glutamine,N (carbobenzy1oxy)glutamic acid y-benzyl ester, and N(carbobenzy1oxy)nitroarginineproved to be very resistant to cleavage. Hydrogenation in acetic acid using 10% palladium on carbon as a catalyst did not remove the Cbz groups from these amino acid derivatives. The use of 70% hydrogen fluoride in pyridine6 also failed to cleave the protecting groups of the glutamic acid ester. The N-t-Boc group of 14 was removed by treatment with hydrogen chloride in dioxane. The N-Cbz group of 9, 11, 12, and 13 was removed by treatment with hydrogen bromide in acetic acid. The amino acid esters were found to be very water soluble, having an aqueous solubility of >200 mg/mL relative to 1,suggesting a lo5 increase in aqueous solubility as the result of this derivatization. Biological Activity. The activity of the lipophilic and hydrophilic esters of 1 is tabulated in Table 11. The greatest differences in antihypertensive activity are seen a t the higher dose levels where some of the esters cause a greater reduction in blood pressure. As illustrated in
200
T 180
LJ
Q 3
2
160
Lu
Q
a
a 0
2
m
I4 0
12c
4
24
8 HOURS
(4) N. F. Albertson, Org. React., 12, 205 (1962).
Figure 1. Effect on blood pressure after administration of 30 mg/kg; ( 0 )100 mg/kg. Points represent compound 2: (0) the average blood pressure of five animals. Vertical bars indicate the standard deviation ( n = 5). For clarity, the bars are shown on only one side of each point for the 0,1,2,4, and 8 h readings.
(5) E. Taschner, M. Smulkowski, and L. Lubiewska-Nakonieczna, Justus Liebigs Ann. Chern., 739, 228 (1970). (6) S.Matsuura, C.H. Niu, and J. S. Cohen, J. Chem. SOC.,Chem. Comrnun., 451 (1976).
Figure 1for 2, the peak effect on blood pressure is at least 8 h postdose. This is true for 1, the lipophilic esters, and the hydrophilic esters.
(3) W. J. Wheeler, D.A. Preston, W. E. Wright, G. W. Huffman, H. E. Osborne, and D. P. Howard, J . Med. Chem., 22, 657
(1979).
Journal of Medicinal Chemistry, 1980, Vol. 23, No. 12 1447
Notes Table 11. Antihypertensive Activity. SHR Model
av blood pressure,a mmHg compd'
PO
dose, mg/kg
predose
4 h PD 1
24 h PD 1
4 h PD 2
24 h PD 2
100 218 173b 185 174 193 213 200 192 164 30 206 150b 132b 122b 143b 2 100 182 15gb 152b 183 165 140 30 162b 181 10 183 149 176 3 205 200 158b 30 202 205 133' 4 181 12gb 30 136b 168 168 142b 162b 137 6 181 30 116b 13gb 7 136 30 173 130' 165 146 154 174 127b 30 8 17gb 50 173b 231 15 17 165 162 189 143 175 177 154 182 145 16 13 170 138b 17 131b 178 124 100 166 164b 12 161b 199 153 164 4 162b 184 189 175 161 15 iac 171 159' 199 183 18 169 15 scd 181 185 166 171 210 21 13 21 5 195 209 215 a-Me-Dopa 161 100 178 155b 174 166 154b 50 187 guanethidine 166b 186 138b a The following compounds (dose mg/kg) did not give a significant lowering of blood pressure at 4 or 24 h postdose (PD): 5 (30 mg/kg), 9-13 (100 mg/kg), 18 (15 mg/kg), 19 (15 mg/kg), 20 (14 mg/kg), and 22 (15 mg/kg). Compound 14 was not screened due to insufficient sample. Indicates that level of significancep =
