Journal $Medicinal Chemistry @ Copyright 1071 by the American Chemical Society
VOLUME14, NUMBER11
Thyroxine Analogs.
NOVEMBER 1971
20.‘ Substituted 1- and 2-Naphthyl Ethers of 3,5-Diiodotyrosine
EUGENE C. JORGENSEN* AND PETER SLADE Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, S a n Francisco, California 94222 Received M a y 11, 1971 The syntheses of 8 substituted 1- and 2-naphthyl ethers of 3,5-diiodotyrosine are reported. 3,3-Diiodo-4-(4-hydroxy-1-naphthoxy )-L-phenylalanine was equiactive with L-thyroxine and 3,s-diiodo-4- (6-hydroxy-2-naphthoxy )L-phenylalanine shoved 257 thyroxine-like activity in the rat antigoiter assay. All other isomeric compounds and analogs were without appreciable thyroxine-like effect. These results indicate that the potential for oxidation to a quinoid form, and steric restrictions on the position of the phenolic OH relative to the “inner” ring are requisites for thyromimetic activity.
The demonstration* that 1- and 2-naphthyl ethers of 3,5-diiodotyrosine possess thyromimetic activity shomed that the phenolic or “outer” benzene ring of thyroxine is not a unique structural requirement. The particularly high activity of 3,5-diiodo-4- (4-hydroxy- 1naphthoxy)-~~-phenylalmine (3,5-diiodonaphthyronine2) may be attributed to the presence of a free OH positioned 1,4 x i t h respect to an ether 0 through an aromatic ring system, and to the naphthalene nucleus being held in a fairly fixed position by steric effects, the most favored position being that in which the plane of the naphthalene ring is at right angles to the plane of the “inner” benzene ring Interaction of the 4’-OH and the “outer” aromatic ring SJ stem xitli a specific part of a biological receptor surface has been postulated3 as an essential step in the production of the biological effects of thyroxine and its analogs. Efficient interaction between such a receptor surface and the 4’-OH-contaiiiing outer ring of 3,5-diiodonaphthyronine would be expected due to the relatively fixed orientation of the naphthalene nucleus. I n addition, the nonhydroxylated ring of the naphthalene moiety may be envisaged as filling spatial, electronic, and lipophilic requirements in its interaction with the receptor surface.j Halogen atoms and alkyl groups niay fulfil this activating function for a substituent on the outer benzene ring in other active thyroxine analogs. Kiemann6 has postulated that the potential for re(1) Paper 19 E C Jorgensen and J Wright, J .Wed Chem 1 3 , 745 (1970) This nork n a s supported b \ Research Grant 4M-04223 from t h e National Institute of i r t h r i t i s and Metabolic Diseases, U S Public Health Service (2) E C Jorgensen and P 4 Lehman, J Org Chem , 26, 897 (1961) ( 3 ) E C Jorgensen P .Z Lehman C Greenberg and %i Zenker, J Bzol Chem , 237, 3832 (1962) (4) P 4 Lehman and E C Jorgensen Tetrahedron 21, 363 (1965) ( 5 ) E C Jorgensen Medicinal C h e m i s t n ” 4 Burger, E d , 3rd ed , l \ i l e k N e i r York i% I , Chapter 31, 1970 (6) C \iemann, Fortschr Chem Or# Xaturst , 7 , 167 (1950)
versible production of a quinoid form is a requisite feature of thyroxine’s interaction with biological systems. In a test of this quinoid hypothesis, thyroxine-like activity was demonstrated for 3,5-diiodo-4-(3,5-diiodo-2hydroxyp1ienoxy)-m-phenylalanine (“ortho-thyroxine”).7 This work and the report of activity for a related 3’-OH analog8 provided support for the concept that no specific r elationship was required between the ether 0 and OH group of thyroxine analogs. The present paper examines these structural and stereochemical concepts further by the synthesis and biological evaluation of a series of 1’- and 2’-naphthyl ethers of 3,5diiodotyrosine bearing an OH group at various positions on the naphthalene nucleus. Possession of thyromimetic activity by such analogs would preclude the interaction between the OH group and a specific part of a receptor surface discussed above. I n addition, 2 types of hydroxynaphthyl ethers are possiblethose from which quinoid forms can be produced, e.g., from the 4’-hydroxy-lr-naphthyl ether, and those from which they cannot, e.y., from the 7’-hydroxy-2’-naphthy1 ether (Scheme I) without the introduction of an additional 0 atom. Thus the activity of 3,j-diiodonaphthyronine is in agreement with Kiemann’s hypothesisS6 1’-Xaphthyl ethers of 3,5-diiodo-~-tyrosinebearing Me and amino groups at the 4’ position were also synthesized. The unsubstituted 1’-naphthyl ether has been shown to be weakly thyromimetic,2but it was postulated that activity may be preceded by in vivo hydroxylation to 3,5-diiodonaphthyronine. The 4’-?\Ie substituted analog was synthesized to investigate this possibility further by the introduction of a group which would block in vivo 4‘-hydroxylation. The 4’-amino(7) P. D. Doyer, C. W.Jensen, and P. H. Phllllps, Proc. SOC.E z p . Bzol. .%fed., 49, 171 (1942). (8) T. C. Bruice, J . Org. Chem., 1 9 , 333 (1954).
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1024 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
SCHEME I
TABLE I
P O T E N T I A L REVERSIBLE OXIDa4TIONOF A
4-HYDROXY-1-NAPHTHYL ETHER(TOP). A 7-HYDROXY-2-NAPHTHYL ETHER(BOTTOM) -1s AN ISOMER WHICH IS NOT OXIDIZED TO THE QUINOID FORM
NAPHTHYL ETHERS
ETHYL ESTI,RA N D
O F ~\‘-ACETYL-3,5-DINITRO-L-TYROSIh L O F ~-~4CETYL-3,~~-DIIODO-L-TYROSINF
ETHYLESTCR R , - O ~ C H 2 ( ! ! H CNHAc 02EX
O
O
R
-+
R2
no quinoid form Ria No.
)“
HO
R
=
-4-(3,5-diiodophenyl)alanine
Yield,
=
R2
substd naphthyl
Mp, O C
%
Optical rotation*
93-95 56 +47.9 NO, 2’-Me0-1’ 131-132 63 +48 6 NO2 4’-Me0-1’ 130-131 41 DL NO, 5’-MeO-l’ 58 +44 2 NO2 151-152 4 6’-Me0-1‘ 160-162 60 +.57 2 NO, 3 7‘-MeO-I’ 17 +69 X NO, 123-127 6 8’-iLIeO-l’ 161-162 70 +5l 0 KO2 7 4’-Me-l’ 60 +9 2 NO2 223-224 8 4’-AcNH-1’ 118-119 71 4-44 6 KO2 9 3’-Me0-2’ 116-118 57 +46 2 KO2 10 S’-RleO-2’ 11 6’-hIe0-2’ SOz 206-207 35 +21 2 12 7’-Me0-2‘ SO, 164-16.5 69 4-44 6 13 4‘-MeO-1’ I 135-137 16 +43 6 14 5’-XeO-l’ I 169-170 4 D I, 13 7’-Me0-1’ I 126-128 13 +70 4 16 4’-?rIe-1’ I 123-12.; 72 +62 2 17 4’-AcNH-l‘ I 2,50-231 29 $44 6 180-182 21 +5t5 4 18 3’-Me0-2‘ I 19 6’-RIe0-2’ I 147-149 18 +31 6 20 7’-MeO-2’ I 171-173 300 21 4’-HO-1’ 83 DL 0 22 5’-HO-l’ 225-227 87 +2-5 0 0 210-212 23 7‘-HO-1’ 91 +63 2 0 24 4’-Me-l’ 243-247 90 +30 0 0 245-247 25 4’-HzN-l’ 87 $20 8 0 261-263 26 3‘-HO-2’ 78 +13 6 2 27 6’-HO-2‘ 252-254 93 $26 6 0 278-281 28 7’-HO-2‘ Compds 21-23, 26-28 (CIgHI&?rT04), 24 (C~OHI~I~XO,), 25 ( C I & ~ I ~ I Z N Z OAll ~ ) . compds were analyzed for C, H, I The values obtd were within 0.4’$& of the calcd values. * [a]26D (L 0 .5, 1 N HC1-EtOH, 1:1 v/v). c Relative to L-thyroxine a b 100 0x1 a molar basis, d The L compd has been described, without a ieport of biological activity, C. 11. Buess, T. Giudici, N. Kharasch, W. King, D. D. Lawson, and N. N. Saha, J . M e d . Chem., 8, 469 (1965).
(9) E. C. Jorgensen and P. Slade, J . .Wed. Pharm. Chem., I , 729 (1962). (10) J. H. Barnes, R. C Cookson, G T. Dickson, J. Elks, and V. D. Poole, J . Chem. Sac., 1448 (1953). (11) R I. Meltzer, D M. Lustgarden, and A. Fischman, J Org. Chem , aa, 1577 (1957). (12) H. Staudinger, E. Schlenker, and H. Goldstein, Helu. Chzm. Acta, 4, 334 (1921). (13) Ng. Ph. Buu-Hoi and D. Lsvit, J . Chem. Soc., 2412 (1956). (14) Detailed biol results are given in Table 111.
that interaction of the OH group with a fairly specifically located part of a receptor surface is a necessary requisite for the thyroxine-like response. The weak activity of the 6‘-hydroxy-2’-naphthyl ether agrees with the idea of such a specific interaction, since molecular models show that the 6’-OH in a 2’-naphthyl ether can
TABLEI1
K ~ P H T H Y LETHERS OF ~ , ~ - D I I O D O - L - T Y R O S I N ~ L R-o-&cH2~Hco2H NHi
I So.
Ri” = substd naphthyl
Yield
Optical
Intigoiter
.\Ip “ C dec
Q
Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11 1025
THYROXINE ANALOGS.20
TABLE I11 RAT ANTIGOITER ASSAY
OF SUBSTITCTED
NAPHTHYL ETHERS O F 3,5-DIIODO-L-TYROSINEa
i Assay number
Daily dose per 100 g, Food
Compound injected
/x
Molar ratio
Thyroid weight 100 g--per mg f s t d dev
Approximate activity
I
Untreated 7.0 1.2 Thiouracil, 0.3% 22.5 4.7 Thiouracil, 0.37, Thyroxineb 2.0 0.67 5.0 13.3 100 Thiouracil, 0 . 37, Thyroxine 1.0 3.0 11.9 6.2 100 Thiouracil, 0. 37, 6.5 1.4 Thyroxine 4.5 100 1.5 Thiouracil, 0 . 37, 0 R = 5’-hydroxy-lt-naphthoxyc 195.0 100 23.9 6.3 0 Thiouracil, 0 . 37, 195.0 100 R = 3’-hydroxy-2’-naphthoxy 26.1 8.0 Thiouracil, 0 . 37, 100 >1.5 R = 6’-hydroxy-2’-naphthoxy 6.0 1.3 195.0 Thiouracil, 0 . 37, 0 R = 7’-hydroxy-2’-naphthoxy 18.5 3.0 195.0 100 6.6 I1 0.8 Untreated Thiouracil, 0. 37, 20.2 3.9 14.4 3.5 Thiouracil, 0.3% Thyroxineb 2.0 0.67 100 10.3 4.0 Thiouracil, 0 . 37, Thyroxine* 1.0 3.0 100 6.1 Thyroxine Thiouracil, 0 . 37, 3.0 4.5 100 1 .5 Thiouracil, 0.37, R = i-‘-hydroxy-l‘-naphthoxy* 23.1 5.9 0 195.0 100 25 Thiouracil, 0.37, R = 6’-hydroxy-2’-naphthoxye -r
