HYPOCHOLESTEROLEMIC THYROALKANOLS
July 1965
47;
TABLE 1 THYROALKANOLS AND THYROALKANOIC ACIDS
yo.
s
nI
1
HO .IcO CHaO H HO HO CHBO CHBO HO
CH3 CHI CHI CHI CHI CHI CHI CH3 CHJ CH3 CHI H
2 3 i 5 6
7
8 9* 10 11
12 13 14' 1.5
16 17 lSd 19' 20 21 22 23
H H HO HO HO HO HO HO HO HO HO HO HO HO
Product R? R~ CHI I CH3 I CHa I CHa I CHa I CHI I CHI I CHI I CHa I CHI I CHI I I€ I I I H I I I I I H I I I I I I I I I H H I H
H H H I H H I
I I H I
+
Recrystn. solvent CHIOH Ethanol C H 1 0 h c Hexane CHzOH Acetone-water CH20H Acetone-water CDzOH Ethanol C O I C H ~ MeOH COL!Ha 1IeOH CO?H Ethanol-water COzH .icetic acid-water COrH Ethanol COzCHa AIethanol CH?OH Acetone CHPOH .Icetone CHgOH Acetone-water CHIOH Methanol-water CH20H Acetone-water CHiOH Acetone-water CHzOH .Icetone C02H CH?OH Acetone CIIzOH Ethanol-water CH20H Acetone-hexane CHzOH CH?Clz-hexane
c/c
T
1
1 1 1 1 1 1 1 1 1 1 1 1
0 0 0 2 2 0 2 3 1
2
a Total D H. British Patent 882,401 (1962). Hegningen, J . Org. Chem., 26, 5005 (1961).
c
X p . , OC. 197.5-198.3 139.5-140.5 134.5-135.5 143-144.5 199-200.5 166.5-169.3 126.0-127.0 203.0-204.0 1514.6-196 219.5-222 108-109.5 182.5-188.5 185.0-186.0 173-174.5 168.5-169 220.5-221.5 192-193 168-169 203-204 dec. 153.5-156.5 117-119 91.5-94
yield 79.5
37.67 40.52 38.95 38.89 37.52 37.94 39.13 37.93
21 64 37 80 41
CiaH11Ig03 Ci;HieI?Oa ClaHi21103 CiiH~11301 Ci3HioI203 C1aH&03 C13Ha1403 ClrHlaI?Oa Ci6H111303
37 82 2 . 7 8 49.06 3 0 . 1 0 3 00 4 8 . 6 1 34.88 2 . 5 1 52.66 27.65 1.82 62.62 33.35 2 . 1 5 54.23 26.37 1 . 5 3 6 4 . 3 2 21.68 1.12 70 52 36.31 2.81 51.16 28.96 2 . 1 0 61.21
85 86 90 67
C16Hd403 C16Hd30a CiaHdOa Ci6Hd803
24 08 25.21 47.21 28.96
95 92 62 62 80 58.5 100 100 79 35 44
67
Lit.z m.p. 185-18i" (benzene).
d
C
Calcd., % H
Formula CMHMIIOI CzoHmI10~ CITHI~IZOI CILHI~I?O? CisHiaD?I?03 C11H1ti120a CisHd?04 CI:HI~~I?OI
3.16 3.40 3.46 3.26 3 54a 2.99 3.28 3 00
1.62 1.88 3.68 2.10
I
49.16 42.82 48.42 51.36 49.56 47.16 47.97 47.16
67 87 66.62 35.63 61 21
C
Found, 'A H I
38.02 40.85 38.81 38.93 37.66 37.96 39.R4 38.03
2.88 3.37 3.65 3.51 3.53 2.87 3,jY 2.66
49.34 43.04 48.58 51.37
37.39
2.72
49.81
46.96 46.88
38 83 8 . 0 8 34.89 27.65 33.33 26.29 21.97 36.16 29.34
48.37 2 . 6 2 32.73 2 . 0 8 62 49 1 . 9 7 54.17 1.33 64.21 1 . 2 7 70 11 2 . 6 1 50.92 2.27 60.78
24.32 25.34 47.43 28.96
1 . 7 4 68 0 2 1 . 8 0 66.88 4 . 0 2 35.34 1.86 61.21
Lit.2 m.p. 165-186" (benzene).
e
E. van
SCHEME I
I
25
I
c\H3
CH3
dH3
I
J
lO,R=H
CHzCOzH
I
I
-
I
CH3
3, R = OCH3 4,R=H
CH3
I
I' 9, R = OCH3
CH3
CH3
26, R = OCH3 27, R = H
1 6
a
i CH3
2
preseuted i i i Table 11. The lollowing structureactivity relationships were drawn from these data. (1) Reduction of a thyroalkaiioic acid (8 or 9) to the corresponding thyroalkanol (3 or 1) had 110 statistically significant effect on hypocholesterolemic activity but
I 1
CH3
1 5
appeared to lower toxicity (ab manifested by inhibitioii of weight gain). ( 2 ) Xethylation of the 4'-hydroxyl group in both the thyroalkanoic acid series (6 us. 7 arid 8 us. 9) arid the thyroalkariols (1 us. 3) had little effect on hypocholesterolemic potency and no con-
\
9 11)
11
di(>ri. OII toxicity.'" (:
