833
THYROJIIUETICS. VI
November 1960
TABLEI SUBSTITUTED 4-PHENOXYPHENYL:\CETIC
AND -PROPIOSIC
ACIDS
x Alp,
Cor11pd no.
n
S
R
Ia b
1 1
c
1 1
NO? NO. NO2 NO2
H 2’,3’-CHs 5,6,7,8-(4H)’ 3’,5‘-CH3 H 2‘,3‘-cH1 H 2‘,3‘-CHa 5,6,7,8-(4Hlc 3‘,5‘-CH3
(1 e f IIa b c (1 e
f IIIa b c d e f
2 2 1 1 1 1
NO?
2 2
1 1 I 1 1
1
1 1
1 1
I
6
IVa
1
1 1 1 1 I
b
1
1
a
CiHs
C2Hs CzHs ClHs CzHs CzHs C2HS CzHs C?Hs H C?Hs C?Hs 2‘,3‘-CH3 H H 2‘,3‘-CH3 H 5,6,7,8-(4H)’ H
NO2 I
1 2 2 1
K’ CiHs
Recrystn
101-102 122-124 94-96 83-85 84-86 119-120 105-106 126-127 85-86
Calcd. %--H Nor1 4.08 8.09 4.99 6.93 5.15 6.51 4.99 6.93 56.66 4 . 4 8 7.78 5 7 . 4 1 5,30 6 . 7 0 37.16 2 . 9 2 49.09 4 0 . 3 1 3.56 44.83 42.59 3 . 7 4 42.86
---
41.40 35.03 36.67 39.29
Found. X--C H Nor1 5 5 . 4 1 4.12 7.96 56.43 5 . 3 0 7.25 58.98 5.33 6.31 56.56 5.07 6.59 56.55 4.55 7.86 57.51 5.37 6.89 37.27 3.00 49.39 40.46 3 . 5 8 44.79 42.81 3.76 43.26
,--
solvent
C 55.49 56.43 58.60 56.43
CHaOH CzHsOH CzHsOH CzHsOH 80% C H I O H C?HsOH CHaOH CzHsOH A q CzHsOH
011
011
94-96 191-193 194-196 218-219
3’5’-CHa
H
H
H
OH
2’,3’-CH, 2‘,3‘-CHa 2’,3’-CHa
OCHa
2’,3‘-CHa
H H (CHdxN(C?H6)2 (CHzIzX- 195-197 (CZH6)Z
196-197 197-199 237-239 lis-179 206-208
Aq CH3OH
CHICK I q CzHsOH CH3COzCzHspetr ether A q CzHsOH CzHsOH CHaCN Aq CzHsOH Acetonehexane
3.82 2.10 2.69 2.93
43.i5 52.87 48.43 46.14
41.85 35.15 36.69 39.44
4.14 2.22 2.87 3.13
36.67 2 . 6 9 36.46 2 . 4 5 37.94 3 . 0 0 3 i . 9 4 3.00 40.05 4 . 2 8
48.43 51.37 47.17 47.17 38.47
36.81 36.i6 38.29 38.27 40.3i
2 . 7 1 48.07 2 . 6 9 51.40 2 . 9 9 47.25 2.96 47.30 4.33 3 8 . 3 5
4.49
37.67
41.16
4.69
41.00
CHaOH(CzHa)zO
Meltiiig points were taken in a Thomas-Hoover capillary melting point apparatus aiid are corrected.
B. Blank arid C. 11.Greenberg, U.S. Patent 3,210,413(Oct 5, 1966).
This is Y
Siedel, H. Nahm, and J . Koiiig, German Patent 1,072,998(Jan 14, 1960).
f
33
.
b
43.59 52.21 48.14 45.56
37.43
Reported previously by
Hemihydrate.
e
Reported by IT’.
Hydrochloride.
TABLEI1 RELATIVE THYROMIMETIC ACTIVITIES= T
Coinpd no.
IIIa b
Y
R
R’
Plasma total cholesterol
Oxygen consumption
Heart wt
increase
Antigoitrogenic
H OH OH OH H OH
H CHzCOOH Inactive 2 ’,3’-CHI CHzCOOH 0.06-0.09 0.014 0.013 0.01 F~,6,7,8-(4H)~ CHzCOOH C 0.025 d 3’,5’-CH3 CHzCOOH 0.025 e H CHzCHiCOOH Inactive f 2’,3’-CH3 CHzCHzCOOH 0.008 2‘,3’-CH3 CHzCOOH g OCHa 0.036 117a OH 2’,3’-CH3 CHzCOOCH&HzN(CzH~)z 0.10-0.15 0,014 0.015 0.01 2’,3’-CH3 b OCH3 CH2COOCHzCHzN(CzHs)z 0.017 0,006 0.003 Inactive S‘a H H bCHzCH(NH2)COOH 0 . 00jc b OH 2 ’,3’-CH3 L-CH&H(NH~)COOH 0.10-0.24c 0.16d 0 . 12d a Activity is expressed in terms of L-T3having an arbitrary value of 1. * This compound is 4-(4-hydroxy-5,6,$,8-tetrahydronaphthoxy)-3,5-diiodophenylacetic acid. This value is comparable to that reported in ref 3. d Value taken from ref 3.
general goal of this investigation mas to determine if previous structure-activity correlations were valid. The syntheses followed the well-established pathways described by Wilkinson8 and Kharasch and coR orkersg for the preparation of 3,5-diiodothyroacetic and -propionic acids. The methoxyphenols required in these ryntlieses ab well a‘ the ether and ester derivn(81 J. H. Wilkinson, Biochem. J . , 63, 601 (1956). (9) N. Iiha1ascl1, S. H. Kalfayan, and J. 1).Arterbarry, J . O r g . Chern. 21, $125 (1056).
tives IIIg, IVa, and IVb were obtained using previously described routes. The reactions are summarized in Chart I, while the compounds prepared, together with appropriate physical constants and analytical data, are presented in Table I.
Experimental Section Methoxyphenols.-2,3-Diniethyl-4-methoxypheiiol was piepared from 2,3-diniethylphenol as described by Joigeiiseii :uid
