The Preparation of Thyroxine Analogues

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PREPARATION C f THYROXINE ANAEOO0ES

by Shih-Ghen Wang

A d iss e r ta tio n submitted in p a r tia l fu lfillm e n t of the requirements fo r the degree o f Doctor of Philosophy, In the Department of Chemistry and Chemical Engineering, in the Graduate C ollege o f the S ta te U n iversity of Iowa February 1950

ProQuest Number: 10666185

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Tv2)‘ aO U )S ^ A 4

Ccxp.Z— ii

AOKHQWI^DGMEHf the w riter w ishes to acknowledge h ie indebted­ ness to Professor Stan ley Wawssonek, h is a d v ise r, fo r the In te r e s t and guidance in th is study and a lso fo r the in ­ valuable a ssista n c e given throughout the e n tir e graduate program • Be a ls o wishes to express h ie gratitu d e to Professor George Glockler* without whose graoious help i t would not have been p o ssib le fo r the w riter to come to study in th is country*

ill ta b le o f cowm m n Fart

Fa$a Introduction . . . . . . . . . . . ....................

X

IX

III

*•.• .....

1

{4*-methoxyphenoxy) cinnamic Acid . . . . . . . . . . . . . . . . ............... .......... * . . . . . . . . . . . . . Statement o f Problem . . . . . . . . . . . . ............. .. •. R esu lts ♦ * * . * , * ............. D iscussion o f Result® . . . . . . . . . . . . . . . . . . . . . Experimental . . Summary ............

8 If 32

sy n th e sis o f Iodine-C ontaining Phenoxyacetic A c id s ......... . . * * . ...................................... H isto rica l .......... R esu lts d iscu ssio n o f R esu lts * • * * . . « • ........ Experimental ............... . . . . ............ *.......... Sum®ary

33 33 35 39 55 70

4 4

§

B io lo g ic a l A ctivity of the Compounds Prepared * * 71

Appendix

A. derivatives of Thyroxine B. Structural Analogues of Thyroxine « C. Relation Between Chemical Constitu tio n and Physiological A ctivity of Thyroxine*-like Com­ pounds ................ . . . . . . . . . 75

Summary of d issertation . . . . . . . . Bibliography . . . . . .

. . . . . . . . . . . 102a . . . . 103

Biography..................*..................... ......... . . . . ............. 110

IV

TABLE OF FIGURES U g a re

page

1.

Abserption spectra of cinnamic acid and aalaetone b ....................................



Absorption spectra of olnnamic acid deriva­ tives and a hydrocinnamic acid related to thyroxine ...... •«»* ......................... 13

3*

Folarograsss of (a) cinnamic acid# (b) 3#5d ilo d o -4 (4 1-hydroxyphenoxy) cinnamic acid and (©) p- ^ S - d lio d o - d - t i1*hydroxyphenoxy)«* phenyl propionic acid (XXII)

12

17



TABUS OF TAMIMS Table 1

w

page

U ltr a v io le t Absorption Maxima fo r Halogen* a te# Cinnamic Acids and Related Compounds in Ithamol *»*•«••*. »**»**«**»•*••. *»««**#••

14

Half-Wave P o te n tia ls and ’D iffu sion Constant C o e ffic ie n ts of S u b stitu ted Cinnamic Acids and Related Compounds In 0«175M Tetrabutyl* ammonium Iodide * 70J4 Dioxane S olu tion

IS

$

Y ield s of fh sn oxyaeetie A c i d s

&2

4

M elting Points and A n alytical Data of Hew Pbenoxyacetlo Acids • • **• • **#• • #• *• • • • ***• • •

@4

5

^ yn oxloe-X ik e A c tiv ity of Cinnamic Acid D eriv a tiv es on Metabolic la t e of Mormal and fbyroidectoinl»ed la t e • * . . * . .......................................71

0

Summary o f E ffe c ts o f Thyroxine Antagon* l e t s ......... *............ . . . . . .............

73

7

D erivatives o f Thyroxine . . . . . . . . . . . . . . . . . . .



S

S tru ctu ral Analogues o f Thyroxine .............

77

0

Thyroidal A c t iv it ie s of Thyroxine Deriva­ tiv e s and Analogues . . . . . . . . . . . . . . . . @ 7

6

10

A ntithyroid and Anti thyrotropic A c t iv it ie s o f Thyroxine Analogues . . . . . . . . . . . . . . . . . . . . .

94

1

m m m m nm I t a ce rta in ensymie rea ctio n la e s s e n t ia l fo r a p h y sio lo g ic a l function# i t i s c le a r th at anything which in te r fe r e s w ith th is enzyme reaction i s lia b le to in h ib it th at function*

I t la w e ll known that an enzyme rea ctio n

can he In h ib ited by fo reig n compounds which compete fo r the enzyme.

I t i s a ls o known^thst the most l i k e ly com*

pounds to ex e rt such a com petitive a ction are those r e ­ la ted s tr u c tu r a lly to the m e ta b e lle a lly important sub­ stan ces a sso cia ted w ith th is enzyme.

th is In terferen ce

concept lead s to a r a tio n a l approach to research in chemo­ therapy (44) * Such an approach i s d irected to making mod­ if ic a t io n s of known e s s e n t ia l m etabolites*

The stru ctu re

o f the e s s e n t ia l m etabolite has to be m odified so as to g ive a compound which I s so c lo s e ly re la ted th at i t can f i t the same enzyme* but which i s s u f f ic ie n t ly unrelated as to be devoid of e s s e n t ia l m etabolic a c tiv ity * Many amino acid analogues have been shown to p ossess a n ta g o n istic e f f e c t s to the amino acid s by v irtu e o f th e ir stru ctu r a l s im ila r ity (133,166*168).

I t Is of

in te r e s t# th erefo re, to determine whether stru ctu r a l ehanges in the thyroxine molecule would give r is e to any sn tith y r e ld a c tiv ity *

The p r a c tic a l s ig n ific a n c e o f th is

a problem cannot be overlooked, Mm* a study of thyroxin# in h ib ition may possibly lea# to the discovery of now ehemotherapeutics fo r the treatment of hyperthyroidism. A survey has' been mad# to l i s t as completely as possible the derivatives and- analogues of thyroxin# prepared and also' th eir physiological a c tiv itie s in those eases where th eir physiological a c t iv it ie s have been re­ ported.

fhe result# of th is survey, which are b riefly

summarised in the appendix, point to the fact that com­ pounds structurally related to thyroxine In general have le s s thyroidal potency than thyroxine i t s e l f 5 and none of them has yet won the d istin ctio n of being an e ffe c tiv e antithyroid. A brief mention is desirable at th is point of Woolleyr# work because i t was the f i r s t attempt made to synthesise struetural analogue® antagonistic to thyroxine. Woolley (1ST) ha® prepared several ether® of W-aeetyldliodotyrosin® which counteract the pharmacological e ffe c t of thyroxine in tadpoles*

HI® observations on the antag­

o n istic 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 fa ile d to

3 f l a t any m i i a l W q p m im

w ith th ese compounds*

'3,B-Mle liodo-4-n itroan ilin e was deamia&ted by treatment o f the diazoniura s a l t w ith ethanol*

The n itr e

group i s known to f a c i l i t a t e the reduction of diaaenium s a lt s by a lco h o ls (131,154) with the formation of l i t t l e or no eth er (123) and very small amounts of ta r .

The

presence of halogens in the aromatic rin g lik ew ise fas* i l i t a t e s th e reducing action of alcoh ols (3 4 ).

The

ethanol method fo r deamination has been applied to iodine compounds w ith favorable r e s u lts (74,157)♦ A ll three di i odon11robenzene a (XXXIX, XLI, and L) were reduced to the corresponding a n ilin e s with stannous ch lorid e in hydrochloric acid*

The correspond­

in g dliodophenoia were then prepared by the replacement of the amino group of these a n ilin e s by hydroxyl* In the h yd rolysis of a diazonlum s a lt to a phenol, u su a lly 40-50$ su lfu r ic acid i s used in order to a tta in a r e flu x temperature s u f f ic ie n t ly high to promote a reasonably rapid reaction*

In the case of io d in e-

45 su b stitu ted amines,. strong a c id ity i s e s p e c ia lly neces­ sary fo r the d ia a o tia a tlo n o f the very weakly b asic amines and fo r the h yd rolysis of the diazonium s a lt s ta b ilis e d by the presence o f the nuclear halogen*

Unfortunately,

use o f strong acid always has a d estru ctiv e action on the phenol produced, p a rticu la rly d iiod o-p h en ols.

A ll

dii©do~phehole in v estig a ted tend to decompose with the lib e r a tio n of iodine a t 6 0 °.

The reaction i s further

complicated by the In e v ita b le contamination with deeply colored by-products, such as aao compounds.

Even though

eteais was admitted to the reaction mixture to minimise the ex ten t of decom position, the crude product was in ­ variab ly a dark o i l .

P u rifica tio n was effe c te d by

(1) ex tra ctio n w ith d ilu te a lk a li, (&) three or four r e ery st& llisa fcions from a large volume of b o ilin g water, (5) d isso lu tio n in ethanol and r e p r e c ip ita tio n , and (4) another r e c r y s ta lliz a tio n from lig ro in *

With 2 ,5 - d i-

iodophenol steam d i s t i l l a t i o n was used in place of step 2.

As a r e s u lt of such treatm ent, the y ie ld s were f r e ­

quently below 50 per c e n t. 2,6-O iiodophenol was prepared by the deamina­ tion of 4~araino~2, 6-diloaophenol (165) which, in turn, was obtained from 4 -n itro -2 ,6 -d iio d o p h en o l.

The la tte r

was obtained from p-nitrophenol by iod in ation with iodine

46 Meaoehloride In a c e tic a c id .

2,6-D iioao-4-n itrop h en ol

was reduced w ith sodium h y d ro su lfite to the diiodeaaino phenol.

According to Grand®ougln (5 3 ), sodium faydro-

s u l f i t e i s e s p e c ia lly u sefu l fo r the preparation of the very s e n s it iv e ©minophenols.

Halogenated nitrophenols

were a ls o reduced (66) by th is reagent*

fhe use of tin

and acid may r e s u lt in the removal of halogen when h alogen*aubstituted nltro*arom atle compounds are reduced (6 5 ). An attempt was made to prepare 2,6-ditQ dophenol by the decarboxylation of 3,5-diiodo-4-hydroxybenzoic acid w ith quin oline and copper chromite*

!o -

tlen a b le ev o lu tio n of carbon dioxide took p lace, but none o f the d esired product was obtained.

3,5-B iiodo^4-

hydroxybenzoic sold was made by io d in a tin g p-hydroxybenzoio acid w ith iod in e atonochlorXde in a c e tic acid (1 6 4 ). 2,3-M iodophenoxyacetlc acid was prepared from 2-lod o-3*n itrop henol by ex a ctly the same sequence o f rea ctio n s p reviou sly employed fo r the preparation of 5-iodophenoxyacetic acid from 3-nitrophenol, namely* the formation of 2-iod o-3-n ltrop h en oxyacetlc acid from the phenol* follow ed by reduction w ith ferrous su lfa te and then a subsequent iandmeyer’ a reaction on 2 -io d o -3 aminophenoxyacetle acid •

This scheme was adopted a fte r

4? I t had been found n ot f e a s ib le to prepare 2 ,3 -d iio a o phenol from 2-1 od o -3 -n i troph en ol•

2-Xodo~3-nitrophenol

r e a d ily gave up io d in e sim ila r to the reported °2-iodQ3H&tawpheiM»l* prepared hy Sohlieper (1 4 0 ).

This la s t

compound was reported to lo se i t s Iodine almost com pletely during the u su al acid reduction*

When 2 - i od o-3-n itrophenol

was reduced w ith sodium h y d r o su lfite , only very low y ie ld s o f tbs amine were obtained*

The high s o lu b ilit y of 2 -

iodo-3-aminophenol i n water and i t s amphoteric nature rendered i t s is o la t io n d i f f i c u l t , e s p e c ia lly in the pres­ ence of a large amount o f inorganic s a lts * The io d in a tio n of m-nitrophenol to 2 -io d o -3 altrop h en ol i s of in te r e s t sin ce i t has been recorded tw ice in the lite r a tu r e *

S eh liep er (140) claimed that

he obtained a new monoiodonitrophenol by the action of io d in e and mercurie oxide m m-nitrophenol in a c e tic acid*

This compound was considered to be 2-iodo~5~

n itro p h en o l, sin ce he had proven that the ch lorin ation of m*mi trophenol gave 2-chloro~3~nitrophenol ♦ This lodo compound, according to S eh lie p e r, was d i f f i c u l t to crys­ t a l l i s e and only once was he able to obtain golden crys­ t a ls which melted a t 134°.

The purity of the product

was q uestionab le sin ce only one o f the two a n a ly tica l

48 data given corresponded roughly to the calcu lated v a lu es. Batta and Proaad (3 9 ), by iod in atin g m -nltrophenol in ammonia s o lu tio n , Iso la ted a compound which melted a t 134® and named I t 2-1od o-3-n itrophenol. Brenans (29) repeated the work of Batta and Prosed and found th a t the 2- i od o-3-n itrophenol previous­ ly described was r e a lly a mixture of $ -io d o -3 -n ltr o ­ phenol and a new 3 -n ttro triio d o p h o a o l.

This iod ln atloa

in ammonia so lu tio n has a ls o been repeated in our lab ­ oratory under various conditions but In every case only an amorphous s o lid , which melted between 118° and 130°, was obtained. 2 - I od o-3-n !trophenol used in our experiments was made by the mensuration of m-lodophenol followed by replacement of the aeetoxymercuri group with io d in e. I t s stru cture was proved by an independent method of sy n th esis which showed i t s o r ie n ta tio n .

2-Amino-3-

n itrop h en ol, whose stru cture has been estab lish ed by Ingold and Ingold (? 2 ), was converted by the Ssndmeyer rea ctio n In to 2 -1 odo-S-nttrophenol.

2-Amino-3-nitro ­

phenol could a lso be prepared by n itra tio n of the d ia c e ty l o-aminophenol follow ed by h yd rolysis.

Aowtylatiea i s important la determining the orien tation In th is reaction*

I t was found by King {80) that the

r e la tiv e o rien tin g power of hydroxyl, aoetoxyl and aoetamino groups In o-aminophenol d eriv a tiv es follow s the order

®i£> M&o > ®&e*

While n itr a tio n of 33-ace t y l -2 -

aminophenol and subsequent hydrolysis gave a mixture of 4 -n itr o - and 6 - n ltro-2-am inophenols, n itra tio n o f 0 ,1 dIacetyl-2-am inophenol follow ed by hydrolysis resulted In a mixture of 3-m itre- and 5-nitro-2-am inophenols which could be e a s ily separated by d ifferen ce in so lu ­ b ilit y * In the In v estig a tio n of the preparation of 0 , H-diacetyI-2-amInophenol, the N -aoetyl d erivative and the ® ,H ,H -trla eety l-d erlv a tlv es were a lso obtained*

D i-

acetyl-2-am inophenol has been prepared by b o ilin g dry amlnophenol hydrochloride with an excess of a c e tic an­ hydride and dry sodium acetate (108) and by heating 0*7 g* o-aminophenol with 0*65 g* a c e tic anhydride in 14 m l. eth y l acetate {18}*

Hepeating the f i r s t method.

50 u sin g th© fr e e aminophenol in stead of the hydrochloride, yield ed the

- t r ia c e t y l d eriv a tiv e which had been

prepared under a sim ila r condition by Diepolder (4 0 ). Be pea tin g the second method led to the production o f the K -acetyl d eriv a tiv e*

The d ia c e ty l compound, however,

Could be e a s ily obtained by heating the aminophenol with a c e tic anhydride alone * 2,4,6*-TriiodophQnoxyacetic acid i s a known com* pound f i r s t prepared by hong and Burger (95) from the 2 ,4 ,6 ~ trilo d o p h en o l*

l o tr iio d ©phenol was iso la te d by

h eatin g the c r y s t a llin e S ,4 ,5 -trilo d 0 b en sen e diaaonium n itr a te (76) e ith e r In water or in aqueous su lfu r ic acid s o lu tio n .

The necessary triiod © an ilin e was obtained

from the corresponding n itr e compound by reduction with stannous ch lorid e and acid in acetone solution* The preparation of 4-amino-3, 5 -d i i odophenoxya c e tic a c id , a p o ssib le interm ediate fo r 3,4,S-trIiod© ~ phenoxyacetic a c id , was unsuccessful*

lod in ation of

p-aminophenoxyacetic acid w ith iodine monochloride In d ilu te hydrochloric a c id , e ith e r a t 90° (as used fo r the lo d in a tio n of 4-aminobensoic acid (SI)) or at room tem­ perature (as used fo r the lod in ation of p-aminophenyla c e tic acid (19)) re su lted only ia tarry products*

For

the preparation of p-aminophenoxyaoetic acid from p-

51 »itrophenoxyacetlo a cid , th© method of reduction with ferrous s u lfa te by Jacobs and leid e lb e r g e r (73) was follow ed w ith certa in m o d ifica tio n s* lo d in a tio n of o -e y eso l and p -e r e se l to the r e sp e ctiv e d iio a o c r e so ls and of reso rcin o l monomethyl eth er to a t r i 1odoras or c I n o l monomethyl ether was accom­ p lish ed by iod in e ia the presence of ammonia (39 ,1 6 3 ). Three general methods have been employed for the preparation of phenexyaeetie acids*

(A 1) Equiva­

le n t q u a n titie s o f th© phenol and monochloroacetic acid were heated w ith a s lig h t excess of sodium hydroxide in water allow ing the so lu tio n to go to dryness; (A 2) the phenol was reflu xed w ith two times the equivalent amount o f monochloroacetic acid and a large excess o f sodium hydroxide in water fo r four hours; and (B) a solution o f the phenol and an excess of sodium butoxide in nbutanol was refluxed w ith e th y l bromoacetate for three hours and the r e s u ltin g product sap on ified . are summarised in Tables 3 and 4 .

The r e su lts

52

fa b le 3 Y ield s o f Phenexyaeetie Acids

S ub stitu en t 2-Xodo 3*1edo 4-I ©do 2 ,5 -B iio d o 2,4-B lied© t*S*0iiCHt© 2,d-011odo S,4-01iodo 3,5-D iiodo 2 ,4 ,6 -fr ilo d © 2 ,4 -D i1odo-6 methyl 2,6-0>iiodo-4methyl 3-K itro 4-ITltro

Method o f frepar* a tio n

Exp&ri mental $ Y ield

AI B At- 1 0 A1 8 A 1 S ill B A I B A I B A1 B

@0.3 68.1 56.0 14.9 96.7 71.4 99.0 12.9 91.6 0 92,3 2 2 .6 78.9 4.85 88.0 0 @7.8

B

00 *1

1 A2 B A1 A2 B

@5.9 79.7 0 0 76.9 0

lite r a tu r e # Yield 15.9 (99) •. ' >’■ 28.5 (82} 38.0 (6 2 ); 38 (99) 3** (114)

74 (95)

61.0 (109)} 34.8»*«- (64) 60 (50)} 0 (82)} 0 (64)

*0 » a s p e c ia l method, such as reduction of a n itr o com­ pound or replacement of amino group by io d in e, d escrib ­ ed in other sectio n s* *#Thls y ie ld was based on the phenol used fo r io d ln a tio n . eeeX ield of the e th y l e s te r of the n itr o a cid .

53 Table 3 (coat*) Y ield s of Pheooxyacette Acids

S ub stitu en t 3-Amlno 4-Amino 5-me thoxy 8*Xede-3~nttr© 2 *ied o-S-aaino 2*6-Dil0do-4~ carboxy 2*0-»-Pi 1odo»4 * n itr o

Method of Prepar­ atio n D J> B

A2 B B A2 B A8 B

Bxperlmental J< Yield

lite r a tu r e % Xieia

70*8 80*4

87.8 (73): SO.3 (109) 92.5 (73); 90 (85)

69.7 79.0 0 61.4 0 0 0 0

•SBNHfr

#-sttH*0btainable by d isso lv in g eth y l 3,5-diiodo-4-hydroxy~ benzoate in absolute alcohol* adding a solu tion o f sodium in absolute alcoh ol and eth y l oh loroacetate, r e f taxing* co o lin g and saponifying (138)*

§4 ta b le 4 Molting P oin ts# end A n alytical Bata of Maw Phenoxyaoetic Acids

JSubatltuents 2,3 -D llo d o 8*5- • 8 ,6 - I 3 ,4 - • 3 ,8 - • 2 ,4 -B iio d o -6 wethyl 2 ,6 -B llo d o -4 methyl 8 ,4 ,S - t r lia d o 3-wethoxy 2 -Io d e -3 -n itr o %- I odo-3-amlno

Empirical Formula

G e H g O g lg

a rt

» 0t% o 3i 2 n

A n alytical Bata Calod, Found %0 % H $ 1 % G 23.78 1.49 » 0 ft tt

to to

0

0

28 >86 1.93

M.P.

2 3 .4 3

1 .2 9 "

23.81 23.90 23.32 23.95

1.47 1.40 1.67 1.84

172-4°## 175-7° 167-©° 179-81° 193-5°

26.12

1 .9 9

205°

0

n

25*79 1.92

168-9°

o 9b7o4i 3

19 *3Q

1 .2 6

29*74

19.83 1.33 29.84 1 . 8 8

2 2 9-30°

C8 H g 0 g H I

08a8°3H1

1.87 32.79 2 #75

182-4° 164°d

#The m alting p oints of known phenoxyacetie acids a l l check c lo s e ly w ith the values In lite r a tu r e with the exception of 8 ,4 ,6 -trlied o p h en o x y a eetie acid which sublimes be­ tween 225-80®* in stead of m elting a t 224-8°$ as reported (9 5 ). #*fh© m elting point of th is substance was depressed more than 30° by the ad dition of any one of i t s f iv e is o ­ meric diiodopfaenoxyacetic acids*

55

For convenience , the reaction s which have been carried out are c la s s if ie d in to the follow in g c a te g o r ie s t A. lo d in a tio n B* Beaaction of n itr o compounds 0* Replacement of amine group by hydrogen B* Heplacement of amino group by iod in e 1* Heplacement of amino group by hydroxyl F * Deearboxylation 0# P ro tectiv e I lt r a t io n H. Condensation*

Formation of phenoxyacetie acids

p*XodQ*Q*ni tr o a n ilin e tffl&'Y} This compound was prepared by the action of Iodine monochloride on o -n itr o a n ilin e in a c e tic acid so lu tio n fo r two hours a t 80° (26) •

Y ield * 52*8$

(L iteratu re, 02*7$)* 0*1 od o*p*altroaallin e (XLI1) This compound was prepared by the action of Iodine monochlorlde on p -n itr o a n ilin e in a c e tic acid so lu a* M elting p oints are not corrected .

56 tio n a t room temperature (160).

Y ield * 58.2$ (L itera­

tu re, no y ie ld given)* 4*Iy6roxy*>3.5^iie6obengoie acid (LXIX) Yhis compound was prepared toy adding Iodine monochloride to p-hydrexybeneoie acid* (LX1 ) In aoeti© a cid , h eatin g the mixture to 80° and m aintaining that temperature fo r 20 minutes (1 6 4 ).

Y ield • 82.0$ (L itera­

tu re, 8 4 $ ). 2.6-0ilodo»»4-nltrophenol (LY) th is compound was prepared toy allow ing Iodine monoehloride to rea ct w ith p-nitrophenol In b o ilin g a c e tic acid for 15 minutes, then d ilu tin g the mixture w ith water and allow ing the reaction to proceed a t 95° fo r 65 minutes (2 2 ).

Yield = 82.6$ (L iteratu re, 8 4 .5 $ ).

$-*4*»Dil.odo*6*methylPhenol (LXXXY) This compound was prepared toy iod ln a tin g oer e so l w ith potassium tr iio d id e In a large excess of ammonia (3 9 ).

Y ield = 87.5$ (L iteratu re, 8 4 .7 $ ).

8.6-M lod o-4-m eth yl phenol (jujXXIl) p-Cresol was iodlnated in a sim ilar manner to ^Prepared toy baking potassium s a lic y la te at 230° and a c id ify in g th© product (3 1 ).

57 that used w ith o*or#sol (3 S ).

Y ield = 90.2$ (L iteratu re,

no y ie ld g iv e n ). 2 .4 , 6*frllodo^-H iethozyohenol (LXXXVIII) Th& lo d in a tio n of reso rcin o l monomethyl ether was carried out by running an asmsoniaeal so lu tio n o f the phenolic eth er and an aqueous so lu tio n of potassium t r i iod ld e at equal ra tes during h a lf hour w ith s tir r in g in ­ to a large volume o f ammonia and continuing th© s tir r in g for two hours (1 6 5 ).

Y ield * 80.5$ (L iteratu re, 80 $ ).

o-Qhloromereuriphenol (XXVI) o-Ohloromereuriphenol was prepared by the marcurafcion o f phenol a t 170° with mercuric a c e ta te , using only phenol as so lv e n t, pouring the mercuration mixture in to hot water and tr e a tin g the so lu tio n with aqueous sodium ch lorid e so lu tio n (168).

Y ield - 45.5$ (L itera­

tu re, 4 4 $ ). o-Iodoohenol (XXVII) o-Xodophenol was prepared by trea tin g o-eh loromeriphenol in chloroform with iodine (169).

Yield * 62.8$

(L ltera tu re, 6 5 $ ). 8 ,4-Dlacetoxvmerourlphenol (XXKVIJ This compound was prepared by s tir r in g phenol

58 w ith a c id ic mercuric a ceta te so lu tio n fo r one hour, wash­ in g the s o lid product w ith water u n t il the washings gave r© tu r b id ity w ith sodium ch lorid e so lu tio n and no pink co lo ra tio n w ith sodium n i t r i t e (5 8 ).

Yield * 35*9$

(L itera ture 8 6 . 6$) * 8 *4-LIlodonhen o l (XXXVII) A so lu tio n of iod in e (53 g*}, potassium iodide (33 g .) and water (300 ml*) was added to a suspension of 2,4-diaoetoxym ercurlphenol (20 g .) in 10$ potassium iodide (300 ml*) and the mixture was stirr ed vigorously fo r h a lf hour*

The product was then f ilt e r e d , washed f i r s t w ith

10$ potassium iodide and next w ith water.

The pink s o lid

on the f i l t e r was d issolved in 100 ml. of ethanol and f ilt e r e d in to 1 kg* of ice-w ater*

The phenol separated

as c o lo r le s s needles upon standing, M.P* 68-70°, and could be used as such fo r the preparation of the phenoxya c e tic acid*

Y ield ® 10*2—10*6 g* (90*2—93*9$)*

I f the rea ctio n mixture was allowed to stand one or two days before the is o la tio n of product by f i l ­ tr a tio n , the product obtained was p r a c tic a lly pure 2 ,4 ,6 -tr ilo d o p h e n o l, M.P. 157-8°, presumably formed through the lo d in a tio n of 2 , 4 -diiodophenol by the excess of Iodine in the m ixture•

58a 8-Aeat^x;3m reupl-3-nf trophenol foXXI) fa a s o lu tio n o f m -nitrophenol (48.5 g .) and sodium hydroxide

(1 0 .4 g .) in water (600 m l.) was added

mercuric a c e ta te

(108 g .) in water (SO0 m l.) , acidulated

w ith a c e tic acid

(10 m l.} .

A fter the mixture had been

warmed on a steam bath and stir r e d vigorou sly for h a lf hour# the product waa f i l t e r e d .

Y ie ld : 185.4 g . (9 0 .4 $ ).

This product could be treated d ir e c t ly with Iodine in the subsequent ste p of s y n th e s is , although r e c r y s t a llis a ­ tio n from g la c ia l a c e tic acid would y ie ld a c r y s ta llin e pr©duet« The product was id e n tic a l in p rop erties to the ace toxymercurini trophenol prepared by the ntereura t i on of m -nitrophenol in ethanol according to the method of Mehta and Ayyar (107)*

However, the y ie ld by th is second method

amounted to only 57 .0 $ . 8 -I od Q-3-stl tronfaen o l (13U1X) 10$ Potassium tr iio d id e so lu tio n (254 g . ) was added gradually w ith s t ir r in g in to a suspension of 2 a ceto x y -3 -n itrophenol (40 g .) in 10$ potassium iodide so lu tio n (250 g . ) .

A fter h a lf hour’ s s tir r in g in the

c o ld , the s o lid product, 2 4 .5 g . (9 2 .1 $ ), was c o lle c te d on the f i l t e r .

A fter r e c r y sta llljsa tio n from water, long

yellow n e e d le s, M.P. 122 -3 °, were formed•

59 2 .4 .6 * T m M co h en o I ( m i l ) This trllodophenol was prepared by the action of hydrogen peroxide ($0$) and potassium Iodide on a hot so lu tio n of phenol in g la c ia l a c e tic acid (101)* Y ields p r a c tic a lly q u a n tita tiv e {Literature* q u an tita tiv e)* B« Reduction of Hjtro gompounds 2.5-D iiodQ anlline C a n ) This compound was prepared by trea tin g 2 ,5 - d lledonltrobeneene w ith stannous chloride and hydrochloric acid at S0° for 2 .5 hours (2 6 ).

Y ields

5 5 .8# (L itera­

ture* no y ie ld g iv e n ). 5 .5 -B llo d o a n liln e (XL) This compound was prepared by the action of stannous ch lorid e and hydrochloric acid on an a lco h o lic so lu tio n of 3 , 5 *dII©d0nitr©benaene (160).

Y ields

91.1$

(L itera tu re, no y ie ld g iv e n ). 5 ,4 -B11 odoan 111 ne (LI) This compound was prepared by tr ea tin g 3 ,4 diiodonitrobenaen© w ith stannous chloride and hydro­ ch lo ric acid a t 100° fo r e ig h t hours (27) • Yields 90.7$ (L itera tu re, 9 0 .2 $ ).

60

r6~ ^ tle d e a n llifie (O T) fills compound was prepared by adding stannous ch lorid e and hydrochloric sold to an acetone so lu tio n of 2 .4 .6 -triio d o n itro b en sen e and refluxim g fo r ten minutes (76) .

n»M «

97.0# (L iteratu re, 96*).

2 .6-Dllodo-4-aralnophonol (LVI) fb is compound was prepared by th© reduction of 2 , 6 ~dilod0~4*'nitrophenol in sodium carbonate so lu tio n with sodium h yd roau lfite (1 6 3 ).

Y ield !

96.6-97.5$

(L itera tu re, 86$ ) . p-Amlnophenoxyacetlc acid (LXIX) A so lu tio n of p-nitrophenoacyacetic acid (4 g . ) In 6 K

(8 ml*) was stir r e d in to a b o ilin g solu tion

of ferrous s u lfa te (46 g#) in water (88 ml#)*

A fter the

so lu tio n was made a lk a lin e w ith cone* ammonia and the mixture b o iled fo r ten minutes, the liq u id was filte r e d in to 11 ml# of g la c ia l a c e tic acid#

On co o lin g , shining

c r y sta ls of the amino-acid separated ou t. (8 0 .4 $ ).

M.P.:

Y ield: 2.73 B*

above 280°, not sharp#

m^Amlnonhenoxyaeetlo acid (XXXI) A so lu tio n of m-nltrophenoxyaeetio acid (4 g*) in ammonia was reduced with ferrous su lfa te in a sim ila r

61 manner to th a t used w ith the p-nitrophenoxyacetic a c id . Y ield :

3 .4 g . (7G*S$).

M.F.: 208°d.

8^Xodo*3^amlnot)henoxyaeetlo acid (LXXX7) 2 ~I©d©-3-nltroph©n0xyao®tlo acid was reduced by the same method ©f reduction used for the m-nitrophenoxya e e tlc a c id , fo llo w s:

the amounts o f reagents employed were as

0 .7 g . of th© n itr o compound in 10 m l. 6$f

ammonium hydroxide, 5 g . ferrous su lfa te In 6 ml. water, 3*4 m l. eomo©fttwate$ ammonium hydroxide and 1 ml. g la c ia l a c e tie a c id .

M.F.: 164®d.

Y ield :

0.39 g . (6 1 .4 $ ).

A n alytical data; o f . fab le 4 .

C, fi.pla 0 8 m.nt of Aailno Sroup by Hydrogen S.8 »D11ofl O-ni trob.cs.no (XXXIX) fhe deamination of 8#6-dii©d©-4*nitr©aniline was accomplished by adding the d lazotized so lu tio n of th is amine to b o ilin g absolute alcoh ol (159).

For the

d ia z o tiz a tio n of the amine, the use of n ltr o e y lsu lfu r lc acid as in the preparation of 3,4,5-triiod ob en aen e (Of. Bart I ) gave a much more s a tis fa c to r y r e s u lt than th© procedure of W illgerodt and Arnold (159) who used pow­ dered sodium n i t r i t e . u ct:

Yield of the r e c r y s ta lliz e d prod­

4 6.7$ (L itera tu re, no y ie ld g iv en ).

62 2 »6- P l1 odonhenol ( M l ) 8 ,©^Dil©d©phen©l was prepared by adding N sodium n i t r i t e to a so lu tio n of 2,©-dlI©ao-4-aMlnQphenol in a lc o ­ hol and r e flu x in g fo r one hour (163)-

I t was e s s e n tia l

to n e u tr a lise the rea ctio n Mixture before the Iso la tio n o f the phenol by steam d i s t i l l a t i o n , otherwise the d llod©phenol would be com pletely decomposed by the acid p resen t.

H eld *

©5*5jS (lite r a tu r e , 52$)*

tolno Orquo by Iodine o-Iodouhsnol (XXUfl This compound was prepared by the d ia so tlsa tla n o f p-amlnophenol and replacement o f the diazonlum group by iod in e (3 8 ).

The amlnophenol, d issolved in d ilu te

su lfu r ic acid, was trea ted w ith an aqueous so lu tio n of sodium n i t r i t e .

Copper bronze was added as a c a ta ly st

for th e replacem ent.

H eld *

50.2$ (L iteratu re, 69-

ni\. 2.5-Dllodonltrobengene (XLV) This compound was prepared by the d la zo tla a tlon ©f p -iod o-o-n itroan ilin © and replacement of the di&zonlum group by iod in e (2 6 ).

h solu tion of the n itr o -

a n illn e In a c e tic a cid , su lfu r ic acid and water was

63 treated w ith an aqueous so lu tio n of sodium n i t r i t e . Y ield 5 97.8$ (lit e r a tu r e , 6 9 .5 $ ). 3.4*Dliodonltrotoenzene (L) This compound was prepared by tbe d ia z o tia a tle n o f p ~n itro-o-iodoanilin© and replacement o f the d im m i\m group by Iodine (8 7 ).

A f in e ly divided suspen­

sion of the amine s u lfa te in aqueous ace t i e acid was treated w ith an aqueous sodium n i t r i t e so lu tio n .

Yields

79.9$ l i t e r a t u r e , 6 7 .6 $ ). ffl-lodophenoxyaeetio aold (XXXII) 4 large excess of powdered sodium n it r i t e (4 .8 g .) was gradually added w ith s tir r in g to a cooled so lu tio n Of m-aminophenoxyace11c sold (4.4 g .) in concen­ trated su lfu r ic acid (45 m l.), while the temperature was kept below 5®. poured in to I c e .

A fter two hours' s tir r in g th© mixture was To the cle a r d iazatized so lu tio n was

added a so lu tio n of potassium iod id e (27 g . ) in water (60 m l.) and the mixture containing a red p recip ita te was warmed on the steam bath for h a lf hour•

A little

sodium b i s u l f i t e was added to remove any iodine present. The s o lid which separated on coolin g was p u rified by d iss o lv in g in 0 .5 ft potassium hydroxide and pouring the a lk a lin e so lu tio n in to an excess of concentrated hydro-

64 ehYorie aoid*

fh® crude product, 4 .1 g . (5 6 .0 $ ), which

melted a t 108-112® gave a c r y s ta llin e product, M.P. 115* 110° , a fte r r c c r y s ta lliz a tio n from benzene. 2 -1 o d o -3 -n ltrophenol ( h m x ) 2-Amino-3-ni trophenol (1.35 g .) in su lfu r ic acid (15 m l.) was treated w ith ©odium n i t r i t e (1 .5 g .) in a sim ila r fash ion a© in the la s t paragraph except that only on©-third of the q u a n titie s of reagent© were used, and the f in a l product was r e c r y sta lliz e d from water in ­ stead of benzene. 1 .4 g . (6 0 .4 $ ).

Y ield of r e c r y sta lliz e d products M.F.i 123-4°.

Anal. Oaled. fo r [email protected]%O5I

H: C, 27.20; H, 1 .5 2 .

Found5 0 , 27.16; H, 1 .6 2 . 9.3-M todophenoxyaoetle acid (&XY) 2-X0do-5 -a®inophenoxyacetic acid (1.3 g .) was d ia zo tized and treated with iod in e by the same procedure used fo r the conversion of m-aminophenoxyacetic acid to ®-iodophenoxyacetlc acid except that only on e-sixth of the amounts of reagents were employed. (9 6 .7 $ ).

Y ield :

1.73 g .

M.F.i 172-4°, which was depressed more than 30°

by the ad d ition of any one of i t s f iv e isom erldes. a ly t ic a l dates

Of. fab le 4 .

An­

60

Qroun tar Hydroxyl Phenol (XLVXl)

2 ,5 -M i ©d©aniline, dissolved ia a mixture of sulfuric acid and acetic sold , was diaaotlaed with solid sodium a it r it e , the Mixture poured into le e , and the hydrolysis was completed by steam -distillin g the produet Yield*

27*9$ (Literature, about 59.8$).

5.4-D iioaonhenol (LIX) 3#4«*Mi©&©anlline in a mixture of su lfu r ic and see t i e a d d was d ia so tise d w ith s o lid sodium n i t r i t e , hydrolysis was carried out f i r s t In le e and la te r by refXuxing th® mixture while a current of steam was passed through (27).

Yield*

27.9$ {L iteratu re, 3 9 .8 $ ).

a.a-M iodophenol (XU) Repeating the o r ig in a l procedure by Brenans (28) resu lted in complete decomposition although Brenans claimed y ie ld s from 59.8 to 4 4 .8 $ .

This compound was

prepared by fo llo w in g the same procedure for i t s 3 ,4 isomer (2 7 ).

Y ield i 28. 6$ .

3 .4 »ff-ffplfod©bengene dlagonium n itr a te (LXYI) friio d © a n ilin e was d issolved in concentrated n it r ic acid and d lagotized In the course of two hours

66 w ith sodium n i t r i t e end the sta b le golden c r y sta ls of the fie ld i

s a l t could toe Iso la ted toy f il t r a t io n {76). q u a n tita tiv e (X Iterature, almost q u a n tita tiv e ). I e &,4 ,© - t r l i 0dophen0l has toeen iso la te d toy

the h y d ro ly sis o f the above diazonium n itr a te under var­ io u s co n d itio n s.

Copper chromite This e a ta ly s t was prepared toy the thermal de­ composition of copper ammonium chromate (9 ). An attempted preparation of 2.6-diiodoi>heaoI (LVII) A thorough mixture of 3,5-aiiod o-4-h ydroxybenzoic acid (5 g .) and copper chromite c a ta ly s t (1 g .) were heated w ith quinoline (10 m l.) in a tube, p a r tia lly surrounded by a su lfu r ic acid bath. sta rted a t 110°.

Decarboxylation

Burlng the f i r s t part of the reaction#

the temperature was leapt between 110*120°.

A fter the

v io le n t rea ctio n was over# the temperature was raised to 120-140°.

A fter one hour1® heating, very l i t t l e

ev o lu tio n o f gas was n o ticea b le and the reaction mixture was extracted w ith benzene*ether m ixture.

The extract

was washed three times w ith 6 N hydrochloric acid to r e -

67 move q u in o lin e , then with water, and f in a lly shaken twice w ith 10$ sodium hydroxide#

The aqueous a lk a lin e so lu ­

tio n was d ilu te d w ith water and f ilt e r e d in to an excess o f concentrated hydrochloric acid#

The colored precip­

i t a t e formed was r e c r y s ta llis e d from 500 ml. b o ilin g w ater.

The c r y s ta llin e product is o la te d , although with

strong phenolic odor, melted above 100° (the desired product should melt a t 68° ) . m 8-Ac e t y l -2 -amin onfaen c l 8-Aminophenol (14 g .) was refluxed fo r two hours w ith a c e tic anhydride (13 m l.) in eth y l acetate (280 m l .) .

A fter most of the solven t was removed by

d i s t i l l a t i o n and the s o lid f il t e r e d , a product which melted a t 202- 6° was obtained.

H eerystalllssotion from

water y ield ed pure 2 -bydroxy-aeetanillde*

fie ld :

1 6.4 g . (9 5 .0 $ ). 0 ,8 .H-Trlaoet y l - 2-amlnophenol (LXXXX) 2-AminophenoI (0.5 mole), was refluxed fo r four hours w ith a c e tic anhydride (2 moles) and sodium acetate (1 m o le).

A fter cooling# a crude product was obtained,

le e r y s t a llia a t lo n from water gave shining, c o lo r le ss

68

n e e d le s, M.P. 7 7 °,

(Pur© triacetyl-2-am lnophenol was

reported t© have a m alting point of 78*8®). ©rude produet*

Yield o f tha

76*7 g . (65*6$).

6f H -M a o etrl-2-am^onhenol (UOC7X) A cetic anhydride (100 ml*) was ca u tio u sly added to 2~am!nophenol (50 g«)«

A fter the a c tiv e reaction was

over, the mixture was refluxed fo r h a lf hour*

fh© ex*

cess of a c e tic anhydride was removed by d i s t i ll a t i o n and a crude product was is o la te d by pouring the residue in to water and f ilt e r in g *

H ecrystaX llsation from water gave

a s o lid which melted a t 124*6°* n t e d products

Yield o f the r e e r y s ta i­

30.0 g. (33*8$).

0>M*01acetvl*3*nltro*2*amimonhenQi (IXTTXI) Placetyl-2~amin©phenol was n itrated with fum­ ing n it r ic acid (d * 1*5) in a c e tic anhydride a t 10° {80}.

The 3 -n itr o d eriv a tiv e was separated from i t s

5 -n ltr o isomer by f i l t r a t i o n .

Y ields

55.5$ (L iterature,

8 . 10$ )• 5*ffttro*2*amlia©rhenoi (LXXVTIX) The 3-n itr o d e r iv a tiv e , obtained above, was hydrolysed by b o ilin g w ith 3 If hydrochloric acid , th© rea ctio n mixture n eu tra lised and th© product filt e r e d

69

and r e c r y e ta llis e d from water (8 0 ).

Y ield

of the red

needles* 88*8$ (lite r a tu r e , y ie ld not g iv e n )• St* Condensation. Formation of ffhenoxyacetio Acids General methods fo r the preparation of phenoxvacefcic acids Al*

Equivalent q u a n titie s of the phenol (0.01

mole) and monoehloroaeetic acid (0 ,01 mole) were heated with a s lig h t excess {0.9 g .) of sodium hydroxide and 10 ml* o f water u n t il the so lu tio n was evaporated to dryness*

the residue was d issolved in 40 ml. of hot

water* the so lu tio n cooled and a c id ifie d with hydrochloric acid#

$he mixture was extracted with eth er, the ether

e x tr a c t washed w ith water and evaporated to dryness on a water hath* A2*

fhe product was r e c r y s ta llis e d from benzene * A so lu tio n o f the phenol (0*1 m ole),

sodium hydroxide (18 g«) and water (78 m l.) was refluxed with monochloroacetlc acid (0*8 mole) for four hours. A fter coolin g the mixture was p u rified toy d isso lu tio n in 6 H ammonium hydroxide and re p rec ip ita tio n toy acid .

*Phe

product was f in a lly r e c r y s ta lliz e d from benzene or from water .e B.

3*1 ml* o f e th y l bromoaeetate was added to

eg-lodo*3*nitrophenoxyacetio acid was r e c r y sta lliz e d from benzene-ethyl a c e ta te .

70 %m phenol i O M m ole), d isso lv e d in a so lu tio n o f nb o ten el {40 ml*) and sodium (0*43 g*) , and the mixture reflu x ed Tor three hours * A fter standing overnight, the e th y l e s te r o f the phenoxyaeetie m m formed was saponi­ f ie d by re.flw&i**g fo r one hour w ith x j *5 ml* o f 30$ so­ dium hydroxide.

the mixture was poured in to aoo el* of

-water and evaporated u n t il the upper o ily layer disappear­ ed*

( I f the sodium s a lt c r y s ta lliz e d out a t th is p oin t,

I t was f i l t e r e d and th e s o lid s a l t suspended in water, a c id ifie d , f i l t e r e d and r e c r y s ta lliz e d as described be­ low}*

The product, p rec ip ita te d by a cid , was Iso la ted

hy f i l t r a t i o n and reery st& llized from b«naene.# Summary For t e s t in g fo r a n tith yroid a c t iv ity three monoi 0dophenoxyacotic a c id s, s i x diiodophenoxyacetic a cid s, one tr11odophsnoxyac® ti c acid and several su b stitu ted lod in o-contain in g phenoxy&eetic acids were prepared*

* The trliodophenoxyacetie acid and the methoxy su b stitu ted triiodophenoxyacetic acid are r e e r y s ta llis e d from alcohol and d ilu te a lc o h o l, r e s p e c tiv e ly ,

71 Part I I I HIOLOGXCAh ACTIVIST OF Till COMPOUNDS PREPARED The fo llo w in g two ta b les were kindly prepared by Dr. Barker.

They represent the b io lo g ic a l a c t iv it y

of some of the compounds prepared and a lso of some r e f­ erence compounds.

72 fa b le 6 Tbyroxlna-like A c tiv ity of Cinnamic Acid D erivatives on Metabolic la to of formal and fhyroiiootom iaod la ta

Compound

t e r cent DB-tfayrcaclne a c t iv ity Iopmal Thypo!dla ta ectojnized Tadpoles

Bp 0 % 0 O * 0 -O 0 iC H C 0 0 H > -COH o

0.2

ClgO 0 * 0 - 0 0B*0WOOS

0.6

Bp

4

0 .2

10

10 O * 0* O OM^amow 1

0 .2

24

10 O - 0- O 0%0%000H

0.2

I

X I HOO - 0 - 0 CH-CHCOOH X I

10

10

200

73 Table 6 Summary of E ffe c ts of Thyroxine Antagonists

Compound lO 0-0% CG 0H

O 0-CH®CQ0H

i

wm of normals s lig h t e f f e c t a t 10•©♦ marked lower­ ing at 105

Teats BME of thyroxine* treated thyroideotomtzed

Estrogen reversal

26# at SOX** 58# at 100X 114# at 500X 105# at

marked e f f e c t at 109 permanent ohange in thyroid

-33# at 500X

85# at 6QQX

O ° - c%cooh

HOOOHbCHCOOH Br HBg

no e f f e c t at 9 no e f f e c t at ai2

J HOO gHoCBCOOH I H%

no e f f e c t at 7 no e f f e c t a t 170

HCOOOOH z

no e f f e c t at 6

-4# at 500X

*mg. drug in ja e te d /k ilo body w t./day **ratl 0 1 OZJ molecular b a s is , of drug to thyroxine

74 Table 6 (c o n t.) Summary of I f fa c ts of Thyroxin© Antagonists

Tests

Compound t H oO o% -caoooH I HH *B-S582“ i

O

A*0

ram of normals

no © ffoct at 6 no o ffo o t at 31

mm ©f thyroxin©** treated thyroidectoraized

Estrogen rev ersa l

82# at 500X 575? at 50X

JJLi OH

o% - oO

I

cooh

66# at lOOOX 64J? a t 1QQX 79J? at 2000X

75

A* I>erlvatlvoa of thyroxine the d e r iv a tiv e s of thyroxine which have been prepared are summarized in fab le 7 . B* S tru ctu ral Analogue a of thyroxin? The stru ctu r a l analogues of thyroxine which have been prepared are summarised in fab le 8 . pounds H ated contain

A ll the com­

(a) iodine or other halogens, (b)

a t le a s t one benaene r in g , (c) an eth er linkage or a hydroxyl group# e ith e r fr ee or e s t e r if ie d , or both, and

(a) a fr e e carboxyl group or a fr ee amino group or both* I t i s to be admitted th at these conditions are very arb itrary and have been proposed only fo r the sake ©f convenience• 0« R elation Between Chemical C onstitution and P hysiological A c tiv ity of Thyroxine-like Compounda A f u l l d iscu s s i on o f th is subject i s given by Barington (57) in h is monograph on the thyroid gland.

He

observes that the presence of certain chemical features in the molecule seems to be respon sible fo r the s p e c ific p h y sio lo g ica l a c t iv it y of thyroxine, namely, i t s iodine co n ten t, the sp e c ia l o rien tation of two of the iodine

76 fa b le 7 D eriv a tives of Thyroxine

Compounds Al A2 A3 A4 AS A6 A7 A8 A9 Al© A ll A12 A15 A14

S a lts of thyroxine w ith a lk a li metals '

f e lt e e r

m

i h q"O )- COOH V.»»'ii«c h o -c h (h hPo p?

Wheeler and Jamieson

BS

lO0C% C00H

Kameli, Gambetta and Rimini 1920

84

i

iX

O

(184)

(99)

Mameli.

oo% ooob

»«8 85

Gambetta and

ir>oc% eooH

(99)

OB( C% ) g

m

Rimini

i

O oe%oo€«

1920

00%

-COOH

2»ehneek 1921

B7

a

B8

H oO oO 0% -°H (K H 2 ) -COOH

Barington 1926

B9

CH3O O 0OCHSCH-COOH

Barington 1926

Br

BIO 0H30 O 0 O »% X

Barington and Barger 1927

(169)

(58)

(61)

78 tab le © (cent*) S tru ctu ral Analogues of thyroxine CoHipound

Reference

B ll

HOOoO^a-CfldTHgJ-COOH X

Barington and larger 1927

(61)

BIS

I I H0O ° O C0°H I I

Harington and Barger 1927

(61)

B13

H C 0 0 O 0 O C % -gH{KH2 )-C00H

Barington 1928

(59)

B14

H0O \

Barington and McCartney 1929

(62)

* \

X3H-CH{NBg )-iCOOH

X K i bib

Br hqO

I oO

gi^

chch^

-

cooh

fe .b 1

Barington and McCartney

B16

HO 01

Schuegraf 1929

(141)

B17

CH30 O 0 O ^ % Br

Schuegraf 1989

(141)

Schuegraf 1929

(141)

Schuegraf 1929

(141)

BIS

Br H 0 O 0O ° % - CH-p { V * Aminophenoxy) phenyl -alanino 024 (BSS) b esiodoaesoxythyro­ nine 023 (B40) 3,S*M loa©4 * (3 I | 8 f *41* lo d o -4 ! -hy~ droxyphenoxy) -phenyl pyruvic a d d 026 (B43) Thyroxine-p* hydroxyphen­ y l eth er 027 (B44) Thyroxine-4 hydroxy-3,5d iiod ©phenyl ether 028 (BSD) 3 ’ ^Pluorothyronine 029 (BS1) 5*-F luoro3,5-d ilod © thyronine 030 (B52) 3*-P in ero­ s ' - i odio-^Sf S*dilodO* thyronine (BSS) p-3*6-61** iodo-4 (2 *, 4 1-d ilo d o 5*-hydroxyphenoxy) phenyl - a l ­ anine

A c tiv ity

Heferenoe I * 0 . Farbcn A. 0 . 1935 (144)

3/11

Can&anelll 1935 (36)

Bovamlek e t +al « Wsw^(zs) a

Cortall

m 9 (37)

1/20 to 1/4 clo se to 100$ b

-{up to 500

agAg)

Cortall

1949 (37)

P hillips

1941 (120)

92 fa b le 9 (c e n t.) fh y ro id a l A c t iv it ie s of thyroxine le r iv a liv e s and Analogues

Compound

Method of assay

032 (B5S) 8 -3 ,5 -D lio do-4 (8 **3*dil©d©-2 *hydroxyphenoxy) phenyl -a lan in e 055 (B60) 8% S*-M flu c r e - 3 ,5 d iio d e -th y ronine 034 (S52) 3S5U D 1* iodothyro­ nine f 035 CB66) S S S '- M i # 0 » 4 (4* hydroxyphenoxy) 3 , 6-d iio d o hippurig acid 036 (B67) S ynthetic thyroxine with l l S i in the 3 1 and 5* p o sitio n s 037 (B6 8 ) G-Cp-Mitroa»c phenyl©thy1 ) I -a e e ty l-$ # 5 dlled© tyrosine a ,c 036 (B69) 0-(p -» ltr o ~ bensyl)-M a e e t y l- 3 ,6 d iio d o ty ro sin e

A c tiv ity 1/25

1/30 to 1 /6

Reference fh iliip s 1041 (120)

Cor t e l l 1949 (37)

- in doses 4X B alter 1042 larger than that of thyrox* ine C o rtell very s lig h t 1949 (57)

same a c t iv it y as nonradio­ a c tiv e syn­ th e tic thy­ roxine *

Cross and Lebland 1948 (35) Woolley e t . a l . 1946 TT67)

fa b le 9 ( c o n t.) f h y r o t d a l A c t i v i t i e s o f fh y ro x in e d e r i v a t i v e s an d A n a lo g u e s

Compound 039 (B73) 3 . 5-Pltoroia0‘4 {4*«*meth«* oxyphenoxy} cinnamic acid 040 (B74) 3 #5*»diiodo*» 4 ( S S B '- a il©do-*4f «*hydroxy~phen~ oxy) phenylgly cin e 041 c a l- Lerman et# a l . 194ST origen ie e f f e c t W7) p itu ita r y -d e ­ pressing e f f e c t Richards e t . nearly the same 1948 as ca lo rig en ic *32) e ffe c t L itzka, % y, In h ib its g ly eo Kraft 1935g en o ly sis pro­ 39 (83,84, duced by thy­ 89-92,102roxine

(Bgi) 5 ,5 * 3 ’ $etrabremothyronine

P9

A c tiv ity

a b

- in exophthal­ mic p a tien ts

f

+

f

150X

a

4

Boyer e t . a l . 195X T »> Kraft Woolley et .a l♦ m r * (i8 7 ) Snapper &£,. a l . 1937 TT46) S a lte r 1940 (135) C o rtell 1949 (37) C o rtell 1949 (37) Woolley e t »a l « I§4S~{167)

96 Table 10 (e o n t.) A ntithyroid and Anti thyrotropic A c t iv it ie s of Thyroxin© Analogues

Qmpmmi 016 (©69) 0-{p-W ttrob en zy l) -Wa e e t y l- 3 ,8 d ilo d o ty ro ­ sin e 017 (B70) O-Beazyl-lla e e t y l- 3 ,8 dliedotyy© sin e

Method of assay

A ctiv ity

Reference Woolley et* a l . 1946” 116

a a

up to kg/day

mg/

Frieden e t . al* 1949” ' T49) Winzler e t . a l . 1948

1X62)

Woolley e t . 018 (©71) O-Butyl-ITa l . 1946 & o© tyl-5,© -dliodotyrosin© Barker a,b C f. Table 5 019 (B73) 3,6-m.brGmo4-(4* -methexyphenoxy )- c in ­ namic acid Winzler e t . 080 (B74) 3 f3-Bii©d©-4- a ,b , a l . 1948 (S V & ^ llG d o - f TT68) 4*-hydroxyphenoxy) -pheny lg ly e in e Prieden e t . ffiBfo-150 021 (B79) O-Benzyl-3, a a l . 1949 5-dilod© 149) tyrosin e Barker Table 6 b ,h 022 (B78) H-(4-hydroxy3 , 6 -diiod©benz­ o yl )