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EP-3927693-B1 - 2-PHENYL-3,5-DIOXO-2,3,4,5-TETRAHYDRO-1,2,4-TRIAZINE-6-CARBONITRILE DERIVATIVES AND SIMILAR COMPOUNDS AS THYROID HORMONE RECEPTOR AGONISTS FOR THE TREATMENT OF E.G. OBESITY

EP3927693B1EP 3927693 B1EP3927693 B1EP 3927693B1EP-3927693-B1

Inventors

  • ZHANG, JUNBO
  • QI, Xiaoxin

Dates

Publication Date
20260506
Application Date
20200220

Claims (16)

  1. A compound of Formula (I) or (Ia), or a tautomer or a pharmaceutically acceptable salt thereof, Wherein: A is O or CH 2 ; B is N or CH; X is O or NR 1 or CHR 1 ; R 1 is selected from bond or H or alkyl; R 2 is H or alkyl; or R 1 and R 2 together with the X-C=C to which they are connected form a 5- to 9-membered carbon or hetero cycle, the hetero cycle is non-substituted or substituted by R 6 and R 7 , R 6 and R 7 are independently selected from the group H or alkyl; R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br and CH 3 ; R 5 is selected from the group consisting of: wherein the alkyl is a C 1 to C 6 -alkyl.
  2. The compound of claim 1, wherein B is CH.
  3. The compound of claim 1, wherein A is O, wherein B is CH.
  4. The compound of claim 3, wherein R 5 is
  5. The compound of claim 4, wherein X is NR 1 or CHR 1 , R 1 and R 2 together with the X-C=C to which they are connected form a 5-membered hetero cycle which is R 6 and R 7 are independently selected from the group H or Me.
  6. The compound of claim 1, wherein B is N.
  7. The compound of claim 6, wherein R 5 is
  8. The compound of claim 7, wherein A is CH 2 , and wherein X is O.
  9. The compound of claim 7, wherein A is O, and wherein X is O.
  10. The compound of any one of the preceding claims, wherein R 2 is i-Pr or Me.
  11. The compound of any one of the preceding claims, wherein R 6 is H, Me, Et or Pr.
  12. The compound of claim 1, selected from one of the following structures:
  13. A compound, wherein said compound has the following structure: or
  14. Pharmaceutical compositions comprising a compound according to any of claims 1-13 and a pharmaceutically acceptable carrier and/or adjuvant.
  15. The compounds according to any of claims 1-13 for use in the therapeutic and/or prophylactic treatment of metabolic diseases.
  16. The compounds according to any of claims 1-13 for use in the therapeutic and/or prophylactic treatment of obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and related disorders and diseases.

Description

BACKGROUND OF THE INVENTION 1. Technical Field The present invention is directed to novel thyroid hormone receptor agonists. The invention is also directed to such compounds for use in treating metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases such as NASH (nonalcoholic steatohepatitis), liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and related disorders and diseases. 2. Description of Related Art Thyroid hormones are hormones produced and released by the thyroid gland. They are primarily responsible for regulation of metabolism and are critical for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitar/thyroid (HPT) axis. They also exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior. The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). TRs belong to the superfamily known as nuclear receptors. TRs form heterodimers with the retinoid receptor that act as ligand-inducible transcription factors. TRs have a ligand binding domain, a DNA binding domain, and an amino terminal domain.TRs regulate gene expression through interactions with DNA response elements and with various nuclear co-activators and co-repressors. TRs are derived from two separate genes, αand β, which can further classified as TRα1, TRα2, TRβ1 and TRβ2. Among them, thyroid hormone receptors α1, β1 and β2 can binding to thyroid hormone. Different subtypes of TRs can differ in their contribution to particular biological responses. For examples, TRβ1 plays an important role in regulating TRH (thyrotropin releasing hormone) and on regulating thyroid hormone actions in the liver; TRβ2 plays an important role in the regulation of TSH (thyroid stimulating hormone) (Abel et. al. J. Clin. Invest.,Vol 104: pp. 291-300 (1999)). Recent studies have revealed that the rational use of thyroid hormones can produce some beneficial therapeutic effects. For example, thyroid hormones increase metabolic rate, oxygen consumption and heat production and thereby reduce body weight. Reducing body weight will have a beneficial effect in obese patients, and may also have a beneficial effect on glycemic control in obese patients with Type 2 diabetes. Other therapeutic benefit of thyroid hormones includes the lowering of the low density lipoprotein (LDL), the increasing of hepatic LDL receptor expression, the stimulating of the metabolism of cholesterol to bile acids, the increasing of HDL cholesterol and the improving of the ratio LDL to HDL. Thyroid hormones also may lower the risk of atherosclerosis and other cardiovascular diseases. With the incidence of obesity and its co-morbidities, diabetes, metabolic syndrome, and atherosclerotic vascular disease rising at epidemic rates, the utility of compounds capable of treating these diseases would be highly desirable. To date, the therapeutic uses of the naturally occurring thyroid hormone have been limited by the adverse side effects associated with hyperthyroidism, especially cardiovascular toxicity. Therefore, efforts have been made to synthesize thyroid hormone analogs which exhibit increased TRβ selectivity and/or tissue selective action. Such thyroid hormone mimetics may yield desirable reductions in body weight, lipids, cholesterol, and lipoproteins, with reduced impact on cardiovascular function or normal function of the hypothalamus/pituitary/thyroid axis. For examples, WO2001060784A1 disclosed aniline-derived ligands of the formula below for the thyroid receptor, Wherein X is-O-, -S-, -CH2-, -CO-, or -NH-; Y is -(CH2)n- where nis an integer from 1 to 5, or cis- or trans-ethylene; R1 is halogen, trifluoromethyl, or alkyl of 1 to 6 carbonsor cycloalkyl of 3 to 7 carbons; R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4carbons or cycloalkyl of 3 to 6 carbons, at least one ofR2 and R3 being other than hydrogen; R4 is hydrogen c or lower alkyl; R5 is hydrogen or lower alkyl; R6 is carboxylic acid or esters or prodrugs; R7 is hydrogen or an alkanoyl or an aroyl. WO2007009913A1 disclosedpyridazinone derivatives of the formula below as thyroid hormone receptor agonists, wherein A is O, CH2, S, SO or SO2;X and Y are each independently selected from the group consisting of Br, Cl and -CH3; R1 is selected from the group consisting of: -(CH2)nCOOH; -OCH2COOH; -NHC(=O)COOH; -NHCH2COOH; Z is H, or -C≡N; R2 is lower alkyl; R3 is H or lower alkyl; n is 1, 2 or 3; p is 1 or 2; or a pharmaceutically acceptable salt or ester thereof. WO2009037172A1 disclosedpyridazinone derivatives of the formula below as prodrugs to thyroid hormone analogs, wherein R1 is -OH, O-linked amino acid, -OP(O)(OH)2 or -OC(O)-R2; R2 is lower alkyl, alkoxy, alkyl