European Patent Office © Publication number 0 188 351 Office europeen des brevets A2 ® EUROPEAN PATENT APPLICATION © Application number: 86300178.0 © mt ci.": C07D 213/64 , C07D 237/14 , C07D 213/65 C07C 103/46 © Date of filing: 13.01.86 , , C07C 101/72 , C07C 149/43 , A61K 31/44 , A61K 31/50 , A61K 31/195 , //C07D237/12 © Priority: 18.01.85 GB 8501372 0 Applicant SMITH KLINE & FRENCH LABORATORIES LIMITED ® Date of publication of application: Mundells 23.07.86 Bulletin 86/30 Weiwyn Garden City Hertfordshire, AL7 1EY(GB) © Designated Contracting States: @ inventor: Leeson, Paul David AT BE CH DE FR GB IT LI LU NL SE 127 Mawson Road Cambridge(GB) Inventor Emmett, John Colin Little Manor Cottage 4 School Lane Weiwyn Hertfordshire(GB) Inventor Underwood, Anthony Hubert 3 The Chase Weiwyn Hertfordshire(GB) Inventor Ellis, David 36 Norton Road Letchworth Hertfordshire(GB) © Representative: Waters, David Martin, Dr. et al Smith Kline & French Laboratories Ltd. Patent Department Mundells Weiwyn Garden City Hertfordshire AL7 1EY(GB) © Chemical compounds. ©@ Compounds Compounds of structure (I) CM < 1ft CO 00 00 Q. HI inin which, R'R1 is -CH2CR2R3NR4R5-CH,CR2R3NR*RS or YCOR6; R2R! is hydrogen hydroxy, Ci^alkoxy,C1-4alkoxy, or -NR4R5; Y is a bond or Ci.C1- oror C1-4alkyl;Ci-4alkyl; R3 is hydrogen or -COR';-COR6; R4R" is hydrogen or ^alkylene;-4alkylene; R' and RsRB are the same or different and are Ci^alkyl;C1-4alkyl; R'Rs is hydrogen, C1-4alkylCi.4alkyl or C1-4alkanoyl;Ci^alkanoyl; R6 is each hydrogen, halogen,halogen. Ci^alkyl,C1-4alkyl, nitro or amino; X is Rank Xerox oxygen, sulphur, or CH2; R9 is hydroxy or a bioprecursor theri20; R10 is hydrogen or G1-4alkyl; and Ar is 4- -hydroxyphenyl, 5-hydroxy-2-pyridyl, 6-oxo-3(lH)-pyridyl or a 6-oxo-3(1 H)-pyridazinyl group and pharmaceutically ac- ceptable salts thereof, processes for their preparation, inter- mediates useful in their preparation, pharmaceutical com- positions containing them and their use in therapy as an- tihyperlipidaemic agents. The present invention relates to novel chemical com- tic Res. 14 , 525, 1972) and T4 and certain thyromimetics pounds, processes for their preparation, intermediates useful have been shown to lower serum cholesterol concentrations in their preparation, pharmaceutical compositions containing in atherosclerotic patients (The Coronary Drug Project Re- them and their use in therapy. search Group, JAMA, 220, 996, 1972). However, the direct The naturally occurring thyroid hormones, 3,5,3'- cardiac effects encountered at doses greater than those -triiodo-L-thyronine (T,) and 3,5,3',5'-tetraiodo-L-thyronine - used in replacement therapy have restricted the widespread (T.) are used in replacement therapy in cases of thyroid use of thyroid hormones and thyromimetic analogues there- deficiency in man. of as therapeutic agents. In addition; thyroid hormones and thyromimetic ana- The compounds of the present invention are structur- logues thereof have been given to individuals with a view to ally related to T3 and T4 and have been found to exhibit treating other conditions (Burrow, G.N., "Thyroid Hormone selective thyromimetic activity. When administered to test Therapy in non-Thyroid Disorders", The Thyroid, Eds Wer- animals, they mimic the effects of thyroid hormones in ner, S.C. and Ingbar, S. H., 4th Edition, Harper and Row, certain tissues at doses which have little or no direct 1978, 974). For example, T, and T4 have been used in the thyromimetic activity on the heart. treatment of obesity (Gwinup, G., and Poucher, R. Am. J. The present invention therefore provides, in a first Med. Sci., 254, 416, 1976, Asher, W.L., Current Therapeu- aspect, a compound of structure (I) in which, Ar is 4-hydroxyphenyl, 5-hydroxy-2-pyridyl, 6-oxo-3(1H)- R' is -CH2CR2R3NR4R5 or YCOR6: -pyridyl or a 6-oxo-3(1H)-pyridazinyl group, R2 is hydrogen or C 1-4alkyl; or a pharmaceutically acceptable salt thereof. Suitably R' is hydrogen; preferably R' is COR6. Suit- R' is hydrogen or -COR'; ably R4 is C1-4alkyl and R' is hydrogen, C1-4alkyl or C1- -4alkanoyl; preferably R4 and R5 are both hydrogen. Suitably R4 is hydrogen or C1-4alkyl; R' is C1-4alkoxy or NR4R5; preferably R' is hydroxy. Suitably Y is a bond. Preferably Y is C1-4alkylene; R5 is hydrogen, C1-4alkyl or C1-4alkanoyl; most preferably Y is methylene, propylene or butylene. Suitably R' and R8 are the same or different and are R6 is hydroxy, C1-4alkoxy, or -NR4R5; each hydrogen, nitro or amino. Preferably R' and R8 are both C1-4alkyl; most preferably R' and R8 are the same and Y is a bond or C1-4alkylene; are each halogen. Suitably X is CH,. Preferably X is sulphur; most prefer- R' and R8 are the same or different and are each hydrogen, ably X is oxygen. halogen, C1-4 alkyl, nitro or amino; Suitably R9 is a bioprecursor of a hydroxy group for example, C1-4 alkoxy, aryl C1-4alkoxy (for example X is oxygen, sulphur, or CH2; OCH2Ph), C 1-4alkanoyloxy (for example OCOCH,), arylC1- -4alkanoyloxy (for example OCOCH2Ph), arylsulphonyloxy - R' is hydroxy or a bioprecursor thereof; (for example toluene sulphonyloxy), alkylsulphonyloxy (for example methane sulphonyloxy), or O-glucuronide; prefer- R10 is hydrogen or C1-4alkyl; and ably R' is hydroxy. Suitably R10 is C1-4alkyl; preferably R10 is hydrogen. Halogen atoms are bromine, chlorine or iodine; prefer- Suitably, Ar is a 4-hydroxyphenyl group or a 5- ably bromine or iodine. -hydroxy-2-pyridyl group. Preferably Ar is a 6-oxo-3(lH)- Compounds of structure (I) can be obtained in the form -pyridyl group; most preferably, Ar is a 6-oxo-3(1H)- of a racemic or diastereomeric mixture or as individual -pyridazinyl group. isomers or mixtures thereof. For example, in compounds of C1-4alkyl groups either alone or as part of another structure (1) in which R2 is hydrogen and R3 is -COR6, the group, for example, C1-4alkoxy or C1-4alkanoyl are methyl, group R is an amino acid residue ethyl, propyl or butyl; preferably, methyl or ethyl. having such a group R' can exist in the form of the D- The present invention includes all isomeric forms in -isomer, L-isomer or DL-mixture of isomers. Suitably, such resolved and unresolved states of the compounds of struc- compounds of structure (I) are provided as the DL mixture ture (I). of isomers; preferably they are provided as the D-isomer or Particular compounds of structure (I) include those L-isomer substantially free of the other isomer. both halogen, R' is hydroxy, R10 is hydrogen and Ar is 6- L-3,5-dichloro-3'-[6-oxo-3(1 H)-pyridazinylmethyl]thyronine. -oxo-3-(1 H)-pyridyl or 6-oxo-3(1 H)-pyridazinyl, for example: 3,5-diiodo-3'-[6-oxo-3(1 H)-pyridylmethyl)thyronine, Further examples of compounds of the present inven- tion include:- 3,5-dibromo-3'-[6-oxo-3(1 H)-pyridylmethyl)thyronine, 3,5-diiodo-3'-[4-hydroxybenzyl]thyronine, 3,5-dichloro-3'-[6-oxo-3(1 H)-pyndylmethyl]thyronine, 3,5-diiodo-3'-[5-hydroxy-2-pyridylmethyl]thyronine, 3,5-diiodo-3'-[6-oxo-3(1 H)-pyridazinylmethyl]thyronine, 4-(4'-hydroxy-3'-(4-hydroxybenzyl)-phenylthio)3,5- 3,5-dibromo-3'-[6-oxo-3(1H)-pyridazinylmethyl]thyronine, -diiodophenylalanine, 3,5-dichloro-3'-[6-oxo-3(1H)-pyridazinylmethyl]thyronine 3,5-dibromo-3'-[6-oxo-3(l H)-pyridylmethyl]thyronine ethyl ester, 4-(4'-hydroxy-3'-(6-oxo-3(1H)-pyridylmethyl)phenylthio)-3,5- -diiodophenylalanine, 3,5-dibromo-3'-[6-oxo-3(1 H)-pyridylmethyl]thyroninamide, 4-(4'-hydroxy-3'-(6-oxo-3(1H)-pyridylmethyl)phenylthio)-3,5- 3.5-diiodo-3'-(6-oxo-3(1 H)-pyridylmethyl)thyropentanoic -dibromophenylalanine; acid, and the foregoing compounds in which the group R' is in 3.5-dibromo-3'-(6-oxo-3(1 H)-pyridylmethyl)thyroethanoic the form of the L-isomer, for example: acid, L-3,5-diiodo-3'-[6-oxo-3(1H)-pyridylmethyl]thyronine, 3,5-diiodo-3'-(6-oxo-3(1 H)-pyridylmethyi)thyrobutanoic acid, L-3,5-dibromo-3'-[6-oxo-3(1H)-pyridylmethyl]thyronine 3,5-dimethyl-3'-[6-oxo-3(1H)-pyridylmethyl]thyronine. L-3,5-dichloro-3'-[6-oxo-3(1 H)-pyridylmethyl]thyronine, N-acetyl-3,5-diiodo-3'(6-oxo-3(1 H)-pyridylmethyl)thyronine, L-3,5-diiodo-3'-[6-oxo-3(1 H)-pyridazinylmethyl)thyronine, 3,5-dibromo-3'-(6-oxo-3(1 H)-pyridylmethyl)thyropropanoic acid. L-3,5-dibromo-3'-[6-oxo-3(1 H)-pyridazinylmethyl]thyronine, Compounds of structure (I) in which R4 and R5 are the potassium or alkaline earth metals for example calcium or same or different and are each hydrogen or C1-4alkyl can magnesium. Further, any carboxy group present can be form acid addition salts with for example, hydrochloric, optionally salified. The ability to form acid addition and/or hydrobromic, hydroiodic, methanesulphonic, or sulphonic metal salts will be subject to the nature of the relevant acids. Acid addition salts can also be formed with the group compounds as will be readily understood by the skilled Ar when it is a nitrogen containing heterocycle. Compounds person. of structure (I) in which R6 and/or R9 are OH can form salts In addition, it will be appreciated that under appropriate with metal ions such as alkali metals, for example sodium or pH conditions, compounds of structure (1) in which R1 is exist as zwitterions. The present invention includes all such zwitterionic forms of the thereof, wherein Ar is (6-hydroxy-3-pyridyl) group;similarly, compounds of structure (I). Similarly, the present invention where Ar is 6-oxo-3(lH)-pyridazinyi, the present invention includes compounds of structure (I) in which the group Ar is includes the tautomeric form thereof wherein Ar is a 6- in the zwitterionic form.