The Preparation of Thyroxine Analogues

119 Pages·06.503 MB·English

by  Wang, Shih-Chen

fm
PREPARATION Cf THYROXINE ANAEOO0ES
by
Shih-Ghen Wang
A dissertation submitted in partial fulfillm ent of the
requirements for the degree of Doctor of Philosophy,
In the Department of Chemistry and Chemical
Engineering, in the Graduate College
of the State University of Iowa
February 1950
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the writer wishes to acknowledge hie indebted­
ness to Professor Stanley Wawssonek, his adviser, for the
Interest and guidance in this study and also for the in­
valuable assistance given throughout the entire graduate
program •
Be also wishes to express hie gratitude to
Professor George Glockler* without whose graoious help
it would not have been possible for the writer to come
to study in this country*
i l l
table of cowmmn
Fart Fa$a
Introduction . . . . . . . . . . . .................... * • . •..... 1
X {4*-methoxyphenoxy) cinnamic
Acid . . . . . . . . . . . . . . . . .........................* . . . . . . . . . . . . . 4
Statement of Problem . . . . . . . . . . . . ............... •. 4
Results ♦ * * . * , * ............. §
Discussion of Result® . . . . . . . . . . . . . . . . . . . . . 8
Experimental . . If
Summary ............ 32
IX synthesis of Iodine-Containing Phenoxyacetic
A cid s ........... * * ....................................... 33
Historical .......... 33
Results 35
discussion of Results *•**..«• . . . . . . . . 39
Experimental ............... . . . . ............*.......... 55
Sum®ary 70
III Biological Activity of the Compounds Prepared * * 71
Appendix
A. derivatives of Thyroxine
B. Structural Analogues of Thyroxine «
C. Relation Between Chemical Con-
stitution and Physiological
Activity of Thyroxine*-like Com­
pounds ................ . . . . . .... 75
Summary of dissertation . . . . . . . . . . . . . . . . . . . 102a
Bibliography . . . . . . .... 103
Biography..................*............................... . . . ............. 110
IV
TABLE OF FIGURES
Ugare page
1. Abserption spectra of cinnamic acid and
aalaetone b .................................... 12
2« Absorption spectra of olnnamic acid deriva­
tives and a hydrocinnamic acid related to
thyroxine ...... •«»* .........................13
3* Folarograsss of (a) cinnamic acid# (b) 3#5-
dilodo-4 (41-hydroxyphenoxy) cinnamic acid
and (©) p- ^S-dliodo-d-ti1 *hydroxyphenoxy)«*
phenyl propionic acid (XXII) 17
▼
TABUS OF TAMIMS
Table w page
1 Ultraviolet Absorption Maxima for Halogen*
ate# Cinnamic Acids and Related Compounds
in Ithamol *»*•«••*.»**»**«**»•*••.*»««**#•• 14
6 Half-Wave Potentials and ’Diffusion Constant
Coefficients of Substituted Cinnamic Acids
and Related Compounds In 0«175M Tetrabutyl*
ammonium Iodide * 70J4 Dioxane Solution IS
$ Yields of fhsnoxyaeetie A cid s &2
4 Melting Points and Analytical Data of Hew
Pbenoxyacetlo Acids ••**••**#••#•*••••***••• @4
5 ^ynoxloe-Xike Activity of Cinnamic Acid
Derivatives on Metabolic late of Mormal and
fbyroidectoinl»ed late •*..*........................................71
0 Summary of Effects of Thyroxine Antagon*
lets .........*............ . . . . . ............. 73
7 Derivatives of Thyroxine . . . . . . . . . . . . . . . . . . . 7®
S Structural Analogues of Thyroxine ............. 77
0 Thyroidal A ctivities of Thyroxine Deriva­
tives and Analogues . . . . . . . . . . . . . . . . @ 7
10 Antithyroid and Anti thyrotropic A ctivities
of Thyroxine Analogues . . . . . . . . . . . . . . . . . . . . . 94
1
m m m m n m
I t a certain ensymie reaction la essential for a
physiological function# it is clear that anything which
interferes with this enzyme reaction is liable to inhibit
that function* It la well known that an enzyme reaction
can he Inhibited by foreign compounds which compete for
the enzyme. It is also known^thst the most likely com*
pounds to exert such a competitive action are those re­
lated structurally to the metabelleally important sub­
stances associated with this enzyme. this Interference
concept leads to a rational approach to research in chemo­
therapy (44) * Such an approach is directed to making mod­
ifications of known essential metabolites* The structure
of the essential metabolite has to be modified so as to
give a compound which Is so closely related that it can
f it the same enzyme* but which is sufficiently unrelated
as to be devoid of essential metabolic activity*
Many amino acid analogues have been shown to
possess antagonistic effects to the amino acids by virtue
of their structural sim ilarity (133,166*168). It Is of
interest# therefore, to determine whether structural
ehanges in the thyroxine molecule would give rise to any
sntithyreld activity* The practical significance of this
a
problem cannot be overlooked, Mm* a study of thyroxin#
inhibition may possibly lea# to the discovery of now ehemo-
therapeutics for the treatment of hyperthyroidism.
A survey has' been mad# to list as completely as
possible the derivatives and- analogues of thyroxin# pre-
pared and also' their physiological activities in those
eases where their physiological activities have been re­
ported. fhe result# of this survey, which are briefly
summarised in the appendix, point to the fact that com­
pounds structurally related to thyroxine In general have
less thyroidal potency than thyroxine itse lf5 and none of
them has yet won the distinction of being an effective
antithyroid.
A brief mention is desirable at this point of
Woolleyr# work because it was the first attempt made to
synthesise struetural analogue® antagonistic to thyroxine.
Woolley (1ST) ha® prepared several ether® of W-aeetyldl-
iodotyrosin® which counteract the pharmacological effect
of thyroxine in tadpoles* HI® observations on the antag­
onistic action of O-hensyl-H-acetyldllodotyrosine toward
thyroxin# have been confirmed by Wlm&ler (162). Wlnzler
also prepared and tasted the glycine homologue and the
bemzpie acid analogue of thyroxine In both of which the
eld# chain of tfeyroxin# has been modified, but failed to
3
fla t any m iia l W qpm im with these compounds*
'3,B-Mle<Ie-# (4r~m$thQxyphm0xy) cinnamie acid,
in which both %m nature of hatXagen tat tea sideehaln of
thyroxine have been altered, was prepared by Waws&nek ant
Lyon (ft)' for testing m a'pesaihls antlthyroid, fhls
compound,' seeerding to BtriEir' tlSl' aioo of, table §),
shewed only a exXghi iByro;3cintriiicf activity*
This present investigation represents a dentin-
nation of the search for possible anti thyroids among thy­
roxine analogues. it was found that - a number of Iodine-
containing phenoxycinn&sai© acid derivatives show approei-
able thyreactivity, while several iodine-containing phen-
©xy&cetle asits markedly lower the 3«K#K« of rats* A de­
tailed account of the preparation of these thyroxine an­
alogues, together with a brief outline of their hioiogioal
activity, w ill he presented in Part® X - III of this dis­
sertation.
4
Part X
QtmmiQ AGID
IndolaGrylio acid (I) hat been found to be a
gpowth^inhlbltery agent far organisms which require
tryptophan (XI) as a growth factor (45) and its Inhibitory
effect ean be overcome by tryptophan (81)* In order to
determine whether such a variation In structure la general
among amino acids In producing antagonistic effects, a
f-w b.tltttt.d M rylio Mia (III) whloh has tb» aam. di-
phenyl ether nucleus as thyroxine, and related compounds
have been synthesised for teating as possible antithyroids*
Q-jO%*GI-O0OH
X. IX*
L x _ Ite. t o
HO O 0 O ^WHMOOH OlaG O 0 O -0®*CHMOQH
X X Br Br
III. XV.
A similar compound (XV) in which the iodine
atoms were replaced by bromine and the hydroxyl group by
methexyl was also prepared•